DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application, in its entirety, claims the benefit of earlier Indian provisional patent application number 2431/CHE/2015 filed on May 13, 2015.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Macitentan.

BACKGROUND OF THE INVENTION
Macitentan (OPSUMIT) is an endothelin receptor antagonist. It is chemically described as N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N'-propylsulfamide or N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'-propylsulfuric diamide. Macitentan is achiral and has the following structural formula-I.

Formula-I
It has been approved by the US Food and Drug Administration and the European Commission for the treatment of pulmonary arterial hypertension.

United States Pat. No. US 7094781 discloses Macitentan and process for the preparation thereof. The last step of its two potential preparation routes described in, called "Possibility A" and "Possibility B", can be summarized as shown in Scheme-A hereafter.

The preparation of Macitentan according to "Possibility B" of US 7094781 has furthermore been described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861, can be summarized as shown in Scheme-B hereafter.

Still there is a need for an improved process for the preparation of Macitentan and the inventors of the present invention developed an improved process for the preparation of Macitentan avoiding hazardous chemicals with non-hazardous chemicals which are easy to handle. The process developed by the present inventors is economical and feasible at industrial level.

SUMMARY OF THE INVENTION
The main object of present invention is to provide an improved process for the preparation of Macitentan.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Macitentan.
In one embodiment, the present invention relates to a process for the preparation of Macitentan comprising the steps of:
1. reacting compound of formula III with ethylene glycol in presence of a base to obtain compound of formula IV

2. reacting compound of formula IV with 5-chloro-2-bromo pyrimidine in presence of a base to obtain compound of formula I [Macitentan].

According to the present invention, the compound of formula III is reacted with ethylene glycol in presence of a base selected from sodium hydride, potassium tertiary butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide or tripotassium phosphate to obtain compound of formula IV which is then reacted with 5-chloro-2-bromo pyrimidine in presence of a base selected from sodium hydride, potassium tertiary butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide or tripotassium phosphate to obtain compound of formula I, Macitentan.

In another embodiment, the process for the preparation of Macitentan according to the present invention is represented by Scheme below:

Scheme-1

The following examples are illustrative of some of the embodiments of the invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

EXAMPLES
Example-1: Preparation of methyl (4-bromophenyl) acetate:

To the solution of (4-bromophenyl) acetic acid (100 .0 g, 0.465 mol) in methanol (500 ml) added conc. sulphuric acid (5.4 g, 0.055 mol) and refluxed for 6.0 hours. The reaction mass was cooled to 25-30 °C and the mass was concentrated under vacuum below 50 °C. The reaction mass was cooled to 25-30 °C. Added dichloromethane (750 ml) and water (300 ml) and stir for 10 min. The layers were separated and aqueous layer was extracted with dichloromethane (250 ml). Combined organic layers were washed with 7 % sodium bicarbonate solution (2 x 100 ml). The organic layer was dried with anhydrous sodium sulphate and concentrated under atmospheric pressure followed by under vacuum to get title compound as viscous oil (105 .0 g, 98.5 %).

Example-2: Preparation of Dimethyl (4-bromophenyl) propanedioate:

To the suspension of sodium hydride (60 % assay, 44.5 g, 1.113 mol) in tetrahydrofuran (500 ml) was added a tetrahydrofuran (180 ml) solution of methyl (4-bromophenyl) acetate (102.0 g, 0.445 mol) drop wise in 120 min. at 25-30 °C and maintained at the same temperature for 45 min. Added dimethyl carbonate drop wise at 25-30 °C in 120 min and maintained at the same temperature for 12 hours. The reaction mass was cooled to 0-5 °C and added dilute hydrochloric acid (136 ml conc HCl in 206 ml water) drop wise at 0-10 °C. Raised the temperature to 25-30 °C and stirred at the same temperature for 20 min. Separated bottom aqueous layer and extracted with ethyl acetate (2 x 250 ml). Combined organic layer washed with water (2 x 150 ml). The organic layer again washed with 5 % triethyl amine solution (2 x 100 ml) and finally washed with water (100 ml).The organic layer dried with anhydrous sodium sulphate and concentrated under vacuum below 45 °C. To the obtained solid added hexane (200 ml) and distilled under vacuum below 45 °C. Added hexane (400 ml) and stirred for 60 min at 0-5 °C. Filter the product, washed with hexane (2 x 50 ml) and dried under air oven for 12 h at 55 °C to get titled compound (100.0 g, 78.24%)

Example-3: Preparation of 5-(4-bromophenyl) pyrimidine-4,6-diol:

To the suspension of dimethyl (4-bromophenyl)propanedioate (80.0 g, 0.278 mol) in methanol (800 ml) was added sodium methoxide solution (25 % in methanol, 180.6 g, 0.835 mol) drop wise at 0-5 °C in 30 min and maintained the reaction mass at the same temperature for 60 min. Added formamidine acetate (34.8 g, 0.334 mol) at 0-5 °C and raised the temperature to 25-30 °C and maintained at the same temperature for 6.0 hours. Distilled the methanol under vacuum below 55 °C resulted semi-solid mass. Cool the mass to 25-30 °C and then added citric acid solution (68.4 g in 800 ml water) drop wise and stirred the mass for 60 min at 25-30 °C. The precipitated product was filtered, washed with water (3 x 160 ml) and dried under air oven at 55 °C for 12 hours to get titled compound (65,0 g, 87.3 %).

Example-4: Preparation of 5-(4-bromophenyl)-4, 6-dichloropyrimidine (II):

The mixture of 5-(4-bromophenyl) pyrimidine-4,6-diol(55.0 g, 0.2059 mol), N,N-dimethyl aniline (55 ml) and phosphorous oxychloride (165 ml) was stirred at 102-105 °C for 4.0 hours. The reaction mass was cooled to 25-35 °C, added dichloromethane (275 ml) and further cooled to 0-5 °C. Water (1100 ml) was added drop wise while maintaining temperature 0-10 °C. Dichloromethane layer separated and aqueous layer extracted with dichloromethane (275 ml). Combined dichloromethane layer was washed with water (2 x 275 ml). The dichloromethane layer stirred with carbon and filtered through hyflo and washed the hyflo wed with dichloromethane. Filtrate was concentrated under vacuum and the product was crystallized with isopropyl alcohol. Filtered the product and dried to afford the titled compound 53.0 g (84.6 %).

Example-5: Preparation of N-[5-(4-bromophenyl)-6-chloropyrimidin-4-yl]-N'-propylsulfuric diamide (III):

To the stirred solution of n-Propyl sulfamide (27.2 g, 0.197 mol) in dimethyl sulfoxide (400 ml) added potassium tertiary butoxide (33.9 g, 0.302 mol) at 25-30 °C and stirred at 40-45 °C 30 min. Added 5-(4-bromophenyl)-4, 6-dichloropyrimidine (40 g, 0.131 mol) at 40-45 °C. The reaction mass was stirred at 40-45 °C for 3.0 hours. The reaction mass was cooled to 1 °C and 1 N HCl (1700 ml) was added drop wise at 10-15 °C, the resulting precipitated product was stirred for 2 hours at 25-30 °C. The product was collected after filtration and dried. The dried product was crystallized with isopropyl alcohol to afford the title compound, 45.2 g (84.8 %).

Example-6: Preparation of N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-N'-propylsulfuric diamide (IV):

The mixture of N-[5-(4-bromophenyl)-6-chloropyrimidin-4-yl]-N'-propylsulfuric diamide (50.0 g, 0.123 mol) and tripotassium phosphate (130.7 g, 0.012 mol) in ethylene glycol (500 ml) was stirred at 120-125 °C for 12.0 hours. The reaction mass was cooled to 25-30 °C. Added acetic acid (110 ml) drop wise at 25-30 °C followed by water (2500 ml). The resulted precipitated product was collect after filtration and then dried. The dried product was crystallized with isopropyl alcohol to get the title compound, 46.5 g (0.75g, 77.1 %).

Example-7: Preparation of N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'-propylsulfuric diamide (Macitentan):

To the solution of N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-N'-propylsulfuric diamide (10.0 g, 0.0231 mol), 5-bromo-2-chloropyrimidine (5.8 g, 0.0301 mol) and tetrabutylammonium bromide(2.24g, 0.006 mol) in dichloromethane (400 ml) was added powder sodium hydroxide (9.2g, 0.23 mol) and refluxed the reaction mass under azeotropic condition for additional 40.0 hours. Cool the reaction mass to 25-30 ºC and added dilute hydrochloric acid (20 ml conc. HCl + 80 ml water). The layers are separated and aqueous layer extracted with dichloromethane (2 x 50 ml). Combined organic layer washed with water (2 x 100 ml) and stirred with carbon (1.0 g) and anhydrous sodium sulphate (5.0 g) for 30 min at 25-30 ºC. Filtered the mass through hyflo bed and washed the hyflo bed with dichloromethane (2 x 20 ml). Filtrate was concentrated under vacuum. Added methanol (30 ml) and distilled under vacuum below 60 ºC. Added methanol (150 ml) and stirred under reflux for 30 min. Cool the mass to 25-30 ºC and stir for 2.0 hours at 25-30 ºC. Filtered the product and washed with methanol (2 x 20 ml) and dried under vacuum at 80 ºC to afford the title compound (9.5 g, 69.8%).

Example-8: Preparation of N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'-propylsulfuric diamide (Macitentan):

To the solution of N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-N'-propylsulfuric diamide (5.0 g, 0.01 mol), 5-bromo-2-chloropyrimidine (2.9 g, 0.01 mol) and tetrabutylammonium bromide(1.12g, 0.003 mol) in dichloromethane (250 ml) was added powder potassium hydroxide (6.5 g, 0.11 mol) and refluxed the reaction mass under azeotropic condition for 48.0 hours. Cool the reaction mass to 25-30 ºC and added dilute hydrochloric acid (10 ml conc. HCl + 40 ml water). The layers are separated and aqueous layer extracted with dichloromethane (2 x 20 ml). Combined organic layer washed with water (2 x 50 ml) and stirred with carbon (2.0 g). Filtered the mass through hyflo bed and washed the hyflo bed with dichloromethane (2 x 10 ml). Filtrate was concentrated under vacuum. Added ethyl acetate (17 ml) and methanol (10 ml) and distilled out completely. Added methanol (40 ml) and stirred under reflux for 30 min. Cool the mass to 25-30 ºC and stir for 6.0 hours at 25-30 ºC. Filtered the product and washed with methanol (2 x 5 ml) and dried under vacuum at 80 ºC to afford the title compound (2.4 g, 35 %).
,CLAIMS:We claim:

1. A process for the preparation of compound of formula (IV),

by reaction of the compound of formula (III)

with ethylene glycol in presence of tripotassium phosphate.

2. The process according to claim 1, further comprising the steps of:
a) the reaction of compound of formula (II) with n-Propyl sulfamide or its salt thereof, in presence of a potassium tertiary butoxide to yield the compound of formula (III).
b) reacting compound of formula III obtained in step a) with ethylene glycol in presence of tripotassium phosphate to yield compound of formula IV.
c) reacting compound of formula IV obtained in step b) with 5-chloro-2-bromo pyrimidine in presence of a base and solvent to give compound of formula-I (Macitentan).

3. The process according to claim 2, where in the base in step c) is selected from the group consisting of sodium hydride, potassium tertiary butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide or tripotassium phosphate.
4. The process according to claim 2, where in the base in step c) is sodium hydroxide.
5. The process according to claim 2, where in the solvent in step c) is dichloromethane.