DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of dofetilide and its intermediates. Dofetilide is N-[4-(2-[2-[4-(Methanesulphonamido)phenoxy]-N-methylethylamino]ethyl)phenyl]methanesulphonamide of following formula:

BACKGROUND OF THE INVENTION
Serious arrhythmias, such as rapid ventricular tachycardia, ventricular fibrillation and sudden cardiac death are a major cause of cardiovascular disease mortality.
Pfizer developed dofetilide as oral anti-arrhythmic medicine against atrial fibrillation.
Dofetilide is disclosed in EP-A-0245997 as an antiarrhythmic agent which has the same patent family US4959366A. The disclosed patent describes a number of synthetic methods for preparing dofetilide.
However, the process described in the above patent for the preparation of dofetilide is tedious and suffers from many disadvantages like poor yield, low purity and not feasible to economical large scale production. To overcome this problem, it is necessary to develop a novel and cost effective process for the preparation of large scale production of dofetilide with high purity.
Thus, the present invention provides a simple, safe and viable process to prepare highly pure dofetilide using novel intermediates or their pharmaceutical salts.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b)

with ethyl chloroformate to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c).

In another object of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting Ethyl methyl (4-nitrophenethyl)carbamate of formula (c)

with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide (d).

In yet another object of the present invention is to provide a process for the preparation of dofetilide comprising steps of:

(a) Nitrating (2-bromoethyl)benzene with nitric acid and sulfuric acid in suitable solvent to obtain 1-(2-bromoethyl)-4-nitrobenzene of formula (a);

(b) Condensing 1-(2-bromoethyl)-4-nitrobenzene of formula (a) with dimethyl amine to obtain N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b);

(c) Reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b) with ethyl chloroformate in suitable solvent to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c);

(d) Reacting Ethyl methyl (4-nitrophenethyl) carbamate of formula (c) with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d);

In yet another object of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III)

with para-toluene sulfonic acid in suitable solvent to obtain para-toluene sulfonic acid salt of 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III).

In yet another object of the present invention is to provide use of compound of formula (c) for the preparation of dofetilide.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b)

with ethyl chloroformate to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c).

In another aspect of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting Ethyl methyl (4-nitrophenethyl)carbamate of formula (c)

with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d).

In yet another aspect of the present invention is to provide a process for the preparation of dofetilide comprising steps of:

(a) Nitrating (2-bromoethyl)benzene with nitric acid and sulfuric acid in suitable solvent to obtain 1-(2-bromoethyl)-4-nitrobenzene of formula (a);

(b) Condensing 1-(2-bromoethyl)-4-nitrobenzene of formula (a) with dimethyl amine to obtain N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b);

(c) Reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b) with ethyl chloroformate in suitable solvent to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c);

(d) Reacting Ethyl methyl (4-nitrophenethyl) carbamate of formula (c) with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d);

In yet another aspect of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III)

with para-toluene sulfonic acid in suitable solvent to obtain para-toluene sulfonic acid salt of 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III).

In yet another aspect of the present invention is to provide use of compound of formula (c) for the preparation of dofetilide.

DETAILED DESCRIPTION

The main embodiment of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b)

with ethyl chloroformate to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c).

In another embodiment of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting Ethyl methyl (4-nitrophenethyl)carbamate of formula (c)

with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d).

In yet another embodiment of the present invention is to provide a process for the preparation of dofetilide comprising steps of:

(a) Nitrating (2-bromoethyl)benzene with nitric acid and sulfuric acid in suitable solvent to obtain 1-(2-bromoethyl)-4-nitrobenzene of formula (a);

(b) Condensing 1-(2-bromoethyl)-4-nitrobenzene of formula (a) with dimethyl amine to obtain N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b);

(c) Reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b) with ethyl chloroformate in suitable solvent to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c);

(d) Reacting Ethyl methyl (4-nitrophenethyl) carbamate of formula (c) with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d);

The suitable solvent for step (a) is selected from toluene, xylene, benzene, ethyl benzene, 1,2-dichloro ethane, methylene dichloride, trichloroethylene, chloroform, carbon tetrachloride, acetic acid or mixtures thereof.

Nitration step (a) is carried out at a temperature below 15°C, preferably from about -5°C to 5°C.

Step (b) is carried out with 40 % aqueous dimethylamine at a temperature of about 25°C to 35°C.

The suitable solvent for step (c) is selected from one or more of toluene, xylene, ethylbenzene, benzene or mixtures thereof.

Step (c) is carried out at a temperature of about 60°C to 70°C and addition of ethyl chloroformate at this temperature.

Step (d) is carried out with aqueous hydrobromic acid at a temperature of about 90°C to 100°C.

In yet another embodiment of the present invention is to provide a process for the preparation of dofetilide comprising a step of reacting 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III)

with para-toluene sulfonic acid in suitable solvent to obtain para-toluene sulfonic acid salt of 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III).
Purification of compound of formula (III) is carried out by preparing p-toluene sulfonic acid salt of compound of formula (III).

The suitable solvent for the preparation of p-toluene sulfonic acid salt of compound of formula (III) is selected from water, toluene, xylene, dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, methanol, ethanol, 1-propanol, isopropanol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate or mixtures thereof.

Salt formation step is carried out at a temperature of about 50°C to 55°C by addition of p-toluene sulfonic acid solution to compound of formula (III).

After the isolation of p-toluene sulfonic acid salt of compound of formula (III), the salt converted into free base of compound of formula (III) by treating with suitable base in suitable solvent. The base used in this step is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. The solvent used in this step is selected from water, methanol, ethanol, isopropanol, 1,2-dichloro ethane, methylene dichloride, chloroform, ethyl acetate, methyl acetate, isopropyl acetate or mixture thereof.

After the purification step, Compound of formula (III) is reduced to compound of formula (II) with transition metal catalyst and hydrazine hydrate in suitable solvent.
Transition metal catalyst for reduction is selected from copper, palladium, rhodium, nickel and suitable solvent for reduction is selected from methanol, ethanol, 1-propanol, isopropanol, butanol or mixture thereof.

Reduction step is carried out at a temperature of about 55°C to 65°C.

Compound of formula (II) is converted into dofetilide by conventional methods by treating compound of formula (II) with methane sulfonyl chloride in suitable base in suitable solvent.

Suitable base for mesylation is selected from triethylamine, dimethylamine, pyridine, piperidine, morpholine and suitable solvent for mesylation is selected from acetonitrile, propionitrile, water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.

Mesylation step is carried out at a temperature of about below 10°C by addition of methane sulfonyl chloride to compound of formula (II).

In yet another embodiment of the present invention is to provide use of compound of formula (c) for the preparation of dofetilide.

The process of present invention is depicted in following schemes.
SCHEME - I

SCHEME – II

SCHEME - III

The following examples illustrate the present invention and as such are not be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLES
Example-1 Preparation of 1-(2-bromoethyl)-4-nitrobenzene
To a solution of acetic acid (10 ml), charge (2-bromoethyl)benzene (10 gm), add sulfuric acid (20 ml) below 30°C. Cool the reaction mass and add nitric acid (4.86 gm) at -5°C to 5°C. Stir the reaction mass for 30 min at -5°C to 5°C. After the completion of reaction charge purified water (100 ml), methylene dichloride (50 ml) in another flask and cool the solution at 5°C to 15°C. Charge above reaction mass into mixture of water and dichloromethane below 30°C and stir the reaction mass for 45 min. Separate the layers and aqueous layer washed with methylene chloride (30 ml). Combined the organic layer and washed with purified water (50 ml) followed by sodium bicarbonate (30 ml). Separate the layers and distilled out organic layer under vacuum below 40°C. Charge 1-propanol (10 ml) and distilled out below 60°C. Charge 1-propanol (10 ml), heat the reaction mass 50°C to 60°C for 30 min. Cool the reaction mass at 25 to 35°C and stir for 60 to 90 min. Filter the product and wash with 1-propanol (5 ml). Dry the product under vacuum.
Dry Weight: 5 gm, HPLC Purity: 99.5 %

Example-2 Preparation of N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine
To a solution of 40% aq.dimethylamine (20 ml), add 1-(2-bromoethyl)-4-nitrobenzene (10 gm) into four equal lots after 30 min. interval. Stir the reaction mass at 25°C to 35°C for 60 to 90 min. After the completion of reaction add methylene chloride (50 ml), stir the reaction mass 45 min at 25°C to 35°C. Separate the layers and wash the aquesous layer with dichloromethane (20 ml). Seperate the layer, Charge combined organic layer and washed with water (2×30 ml). Distilled out organic solvent under vacuum below 40°C. Charge toluene (10 ml) and distilled out under vacuum below 50°C. Unload the liquid material.
Dry Weight: 8.4 gm, HPLC Purity: 98.0%.

Example-3 Preparation of ethyl methyl (4-nitrophenethyl) carbamate.
To a solution of toluene (50 ml), charge N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine (10 gm), heat the reaction mass at 60°C to 70°C. Add ethyl chloroformate (10 ml) at 60°C to 70°C. Stir the reaction mass for 90 to 120 min. at 60°C to 70°C. After the completion of reaction cool the reaction mass to room temperature and charge purified water (10 ml) and stir for 30 min. Separate the layer and distilled out organic layer under vacuum below 60°C. Charge the cyclohexane (30 ml), cool the reaction mass to 5°C to 10°C and stir for 60 to 90 min. Filter the product and wash with cyclohexane (10 ml). Dry the product under vacuum.
Dry Weight: 9.3 gm, HPLC Purity: 99.0%.

Example-4 Preparation of N-methyl-4-nitrophenethylamine hydrobromide
To a solution of aq. Hydrobromic acid (30 ml), add ethyl methyl (4-nitrophenethyl)carbamate (10 gm), heat and stir the reaction mass at 90°C to 100°C for 240 min. After the completion of reaction purging nitrogen to remove hydrogen bromide gas. Distill out water till slurry volume under vacuum at 60°C to 70°C. Charge toluene (50 ml) heat the reaction mass to reflux to remove water by dean-stark distillation. After complete removal of water distilled out toluene till slurry volume. Cool the reaction mass and charge ethyl acetate (30 ml) at 25 to 35°C. stir the reaction mass at 25 to 35°C for 45 min. Filter the product and wash with ethyl acetate (10 ml). Dry the product under vacuum below 50°C.
Dry Weight: 9.3 gm, HPLC Purity: 99.0%.

Example-5 Preparation of 1-(2-bromoethoxy)-4-nitrobenzene
To a solution of water (70 ml), 4-Nitro phenol (10 gm), 1,2-dibromoethane (13.5 gm) potassium carbonate (10 gm), heat and stir reaction mass at 90 to 100°C for 4 to 5 hrs. After the completion of reaction cool the reaction mass and separate the layer. Distill out solvent under vacuum to obtain residue. Add 1-propanol (60 ml) to above residue and stir the reaction mass for 30 to 45 min. Filter the product and distill out filterate to obtain residue. Charge cyclohexane to residue and stir the reaction mass for 30 to 45 min at 25 to 35°C. Filter the product and wash with cyclohexane (10 ml). Dry the product under vacuum below 35°C.
Dry Weight: 12 to 14 gm

Example-6 Preparation of 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-
nitrophenethyl)amino]ethane
To a solution of acetonitrile (70 ml), N-methyl-4-nitrophenethylamine hydrobromide (10 gm), Potassium Carbonate (13.21 gm), heat the reaction mass 70 to 80°C and add 1-(2-bromoethoxy)-4-nitrobenzene solution (11.31 gm in 300 ml acetonitrile) during 60 to 90 min. Heat and stir reaction mass 70 to 80°C for 6 to 7 hrs. After the completion of reaction cool the reaction mass and filter, distill out filterate and charge methanol (30 ml) and again distill out to obtain residue. Charge methanol (30 ml) to residue and stir for 3 to 4 hrs at 10 to 15°C. Filter the product and wash with methanol (10 ml). Add acetone (50 ml) to wet material heat and stir reaction mass at 50 to 55°C for 10 to 15 min. Charge PTSA solution (7.28 gm PTSA in 20 ml acetone) and stir 20 to 30 min at 50 to 55°C. Cool the reaction mass 25 to 30°C and stir for 60 to 90 min. Filter the product and wash with acetone (10 ml), suck dry well. charge water (50 ml) and methylene chloride (50 ml) to wet material. Adjust the reaction mass pH 9 to 11 with sodium hydroxide solution stir the reaction mass 20 to 30 min at 25 to 35°C. Separate the layer and distill out organic layer below 70°C to obtain residue. Charge methanol (20 ml) to residue and stir 60 to 90 min at 25 to 35 °C. Filter the product and wash with methanol (10 ml). Dry the product under vacuum below 35°C.
Dry Weight: 8 to 10 gm

Example-7 Preparation of 1-(4-Aminophenoxy)-2-[N-(4-aminophenethyl)-N-
methylamine]ethane
To a solution of methanol (150 ml), 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-
nitrophenethyl)amino] ethane (10 gm), 10% Palladium on Charcoal (2 gm) under nitrogen, charge hydrazine hydrate lot wise (4×2.5 ml). Heat the reaction mass at 55 to 65°C for 5 to 6 hrs. After the completion of reaction filter the reaction mass and distill out filtrate under vacuum below 50°C. Charge toluene (20 ml) and distill out under vacuum two times to obtain residue. Charge toluene (20 ml) and stir the reaction mass 30 to 60 min at 25 to 35°C. Cool the reaction mass 5 to 10°C and stir for 60 to 90 min. Filter the product and wash with toluene (10 ml). Dry the product under vacuum below 35°C.
Dry Weight: 7 to 8 gm

Example-8 Preparation of 1-(4-Methanesulphonamidophenoxy)-2-[N-(4-
methanesulphonamidophenethyl)-N-methylamino] ethane
To a solution of acetonitrile (80 ml), 1-(4-Aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (10 gm), TEA (7.09 gm), cool the reaction mass at 0 to 10°C and stir for 10 to 15 min. Add methane sulfonyl chloride solution (8.02 gm in 20 ml acetonitrile) below 10°C and stir reaction mass 60 min below 10°C. After the completion of reaction charge water (50 ml), Sodium carbonate (20 ml) and stir 15 to 30 min. Distill out acetonitrile below 50°C. Charge water (30 ml), Sodium hydroxide solution (15 gm sodium hydroxide in 30 ml water) to adjust pH above 12. Stir reaction mass 25 to 35°C for 3 hrs. Add Conc. HCl (30 ml) to adjust pH 7 to 8 and stir 90 to 120 minutes at 25 to 35°C. Filter the reaction mass and wash with water (2×10 ml). Charge purified water (100 ml) to wet material and stir 60 to 90 min at 25 to 35°C. Filter the product and wash with purified water (2×10 ml). Dry the product under vacuum below 60°C.
Dry Weight: 12 to 14 gm ,CLAIMS:1. A process for the preparation of dofetilide comprising a step of
reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b)

with ethyl chloroformate to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c).

2. A process for the preparation of dofetilide comprising a step of
reacting Ethyl methyl (4-nitrophenethyl)carbamate of formula (c)

with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d).

3. A process for the preparation of dofetilide comprising steps of:
(a) Nitrating (2-bromoethyl)benzene with nitric acid and sulfuric acid in suitable solvent to obtain 1-(2-bromoethyl)-4-nitrobenzene of formula (a);

(b) Condensing 1-(2-bromoethyl)-4-nitrobenzene of formula (a) with dimethyl amine to obtain N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b);

(c) Reacting N, N-dimethyl-2-(4-nitrophenyl)ethan-1-amine of formula (b) with ethyl chloroformate in suitable solvent to obtain ethyl methyl (4-nitrophenethyl) carbamate of formula (c);

(d) Reacting Ethyl methyl (4-nitrophenethyl) carbamate of formula (c) with hydrobromic acid to obtain N-methyl-4-nitrophenethylamine hydrobromide of formula (d);

4. The process as claimed in claim 3, wherein suitable solvent for step (a) is selected from methylene chloride, trichloroethylene, carbon tetrachloride, acetic acid or mixtures thereof.

5. The process as claimed in claim 3, wherein suitable solvent for step (c) is selected from toluene, xylene, benzene or mixtures thereof.

6. A process for the preparation of dofetilide comprising a step of reacting 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III)

with para-toluene sulfonic acid in suitable solvent to obtain para-toluene sulfonic acid salt of 1-(4-Nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane of formula (III).

7. The process as claimed in claim 6, wherein suitable solvent is selected from water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.

8. Use of compound of formula (c) for the preparation of dofetilide.