DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF MACITENTAN”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of macitentan.

BACKGROUND OF THE INVENTION
Macitentan, also known as N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide, is represented by the structure of formula I.

Macitentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
The object of the present invention is to provide a process for the preparation of macitentan with improved yield and purity.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of macitentan, a compound of formula I,

the process comprising:
(a) reacting a compound of formula V with a compound of formula VI, wherein M is selected from Li, Na, K,

in the absence of a base and at a temperature in the range of about 40°C to about 150°C to give a compound of formula IV,
;
(b) reacting the compound of formula IV with ethylene glycol to give a compound of formula II,

wherein, the compound of formula II is isolated from non-ketonic solvents; and
(c) reacting the compound of formula II with a compound of formula III,

in the presence of a base selected from alkali metal hydroxides or alkaline earth metal hydroxides, to give macitentan, the compound of formula I.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of crystalline macitentan as obtained in Example 8.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of macitentan, a compound of formula I,

the process comprising:
(a) reacting a compound of formula V with a compound of formula VI, wherein M is selected from Li, Na, K,

in the absence of a base and at a temperature in the range of about 40°C to about 150°C to give a compound of formula IV,
;
(b) reacting the compound of formula IV with ethylene glycol to give a compound of formula II,

wherein, the compound of formula II is isolated from non-ketonic solvents; and
(c) reacting the compound of formula II with a compound of formula III,

in the presence of a base selected from alkali metal hydroxides or alkaline earth metal hydroxides, to give macitentan, the compound of formula I.
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
In (a) of the process for the preparation of macitentan, the compound of formula V is reacted with the compound of formula VI, wherein M is selected from Li, Na, K, in the absence of a base and at a temperature in the range of about 40°C to about 150°C to give the compound of formula IV.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof. Preferably, the solvent selected is dimethyl sulfoxide.
The reaction of the compound of formula V with the compound of formula VI in the presence of a base reduces the yield of the reaction. Further, reacting the compound of formula V with the compound of formula VI at a temperature lower than 40°C requires a longer reaction time and results in a lower product yield. It was found that the reaction between the compound of formula V and the compound of formula VI proceeded in shorter reaction time with excellent yields at a temperature in the range of about 40°C to about 150°C and in the absence of a base.
In one embodiment, the compound of formula V is reacted with the compound of formula VI, wherein M is K, in the absence of a base and at a temperature in the range of about 50°C to about 80°C to give the compound of formula IV.
In (b) of the process for the preparation of macitentan, the compound of formula IV is reacted with ethylene glycol to give the compound of formula II, wherein, the compound of formula II is isolated from non-ketonic solvents.
The reaction may be carried out in the presence of a suitable base. A suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkali metal such as sodium metal; alkyl lithium such as n-butyl lithium. Preferably the base selected is potassium tert-butoxide.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof.
The compound of formula II is isolated from non-ketonic solvents. The non-ketonic solvents may be selected from the group consisting of alcohols such as ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like, ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile; hydrocarbons such as toluene, xylene, heptane, hexane and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; or mixtures thereof. Preferably, the non-ketonic solvent selected is isopropyl alcohol, tert-butyl methyl ether, or mixture thereof.
In one embodiment, the compound of formula II is obtained with ethylene glycol content in the range of about 15 ppm to about 30 ppm.
In one embodiment, the present invention provides N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide, a compound of formula II, prepared by process as described herein, in a purity of =99.0% and wherein the level of one or more compounds of formula A, formula B, formula C and formula IV is less than 0.15%.


In one embodiment, the present invention provides N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide, a compound of formula II, prepared by process as described herein, in a purity of =99.0% and wherein one or more compounds of formula A, formula B, formula C and formula IV are absent.
In (c) of the process for the preparation of macitentan, the compound of formula II is reacted with the compound of formula III, in the presence of a base selected from alkali metal hydroxides or alkaline earth metal hydroxides to give macitentan, the compound of formula I.
The alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, the alkaline earth metal hydroxides include magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide. Preferably the base selected is sodium hydroxide.
In one embodiment, the compound of formula II is reacted with the compound of formula III in the presence of sodium hydroxide.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof. Preferably, the solvent selected is toluene-dimethyl formamide mixture.
The use of sodium hydride or potassium tert-butoxide as a base in the reaction of the compound of formula II with the compound of formula III imparts dark colour to the reaction mixture resulting in a coloured product. Charcoalisation of the reaction mixture becomes indispensable to remove the colour impurity which decreases the yield of the product, increases the number of steps and cost thereby. Surprisingly, the reaction of the compound of formula II with the compound of formula III using alkali metal hydroxide or alkaline earth metal hydroxide as a base does not result in coloured impurity, thereby yielding a colourless product and minimizing the charcoalization step.
In one embodiment, the present invention provides a process for the preparation of macitentan, a compound of formula I, the process comprising:
(a) reacting a compound of formula V with a compound of formula VI, wherein M is is K, in the absence of a base and at a temperature in the range of about 50°C to about 80°C to give a compound of formula IV;
(b) reacting the compound of formula IV with ethylene glycol to give a compound of formula II, wherein, the compound of formula II is isolated from isopropyl alcohol; tert-butyl methyl ether; or mixture thereof and
(c) reacting the compound of formula II with a compound of formula III, in the presence of sodium hydroxide to give macitentan, the compound of formula I.
In one embodiment, the present invention provides a process for the preparation of macitentan, a compound of formula I, the process comprising: reacting compound of formula II with the compound of formula III, in the presence of a base selected from alkali metal hydroxides; alkaline earth metal hydroxides; alkali metal carbonates; alkaline earth metal carbonates; alkali metal bicarbonates to give macitentan, the compound of formula I.
The alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, the alkaline earth metal hydroxides include magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, the alkali metal carbonates include sodium carbonate, potassium carbonate, caesium carbonate; and alkali metal bicarbonates include sodium bicarbonate.
In one embodiment, the present invention provides a process for the preparation of macitentan, a compound of formula I,

the process comprising:
(a) reacting a compound of formula V with a compound of formula VI, wherein M is selected from Li, Na, K,

in the absence of a base and at a temperature in the range of about 40°C to about 150°C to give a compound of formula IV,
;
(b) reacting the compound of formula IV with ethylene glycol to give a compound of formula II,
; and
(c) reacting the compound of formula II with a compound of formula III,

in the presence of a base selected from alkali metal hydroxides or alkaline earth metal hydroxides, to give macitentan, the compound of formula I.
The reaction conditions are as discussed supra.
In one embodiment, the present invention provides macitentan with ethylene glycol content below detection limit.
In one embodiment, the present invention provides macitentan with purity of at least 99.9% w/w, as determined by HPLC.
In one embodiment, the present invention provides macitentan free of any of the below listed compounds A-F, II, III, IV.

wherein in F, R = H, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2NHCH2CH3.
In one embodiment, the present invention provides macitentan in a purity of =99.0% and wherein one or more compounds A-F, II, III, IV are absent.
In one embodiment, the present invention provides pharmaceutical compositions comprising macitentan or salt thereof obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state macitentan into any of the foregoing desired particle size range.
In one embodiment, the present invention provides pharmaceutical compositions comprising macitentan or salt thereof, having a D50 particle size of about 250 microns to about 400 microns.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

EXAMPLE 1 Preparation of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl) propane-1-sulfamide
To a stirred mixture of 5-(4-bromophenyl)-4,6-dichloropyrimidine (50g) in dimethyl sulfoxide (225mL) was added a mixture of propane-1-sulfamide potassium salt (58g) in dimethyl sulfoxide at about room temperature. The reaction mixture was heated to about 50°C to about 55°C and stirred for about 1h. The reaction mixture was cooled to about room temperature and water and hexane were added to it. The reaction mixture was stirred and the two layers were separated. Aqueous hydrochloric acid was slowly added to the aqueous layer at about room temperature to give off-white slurry. The reaction mixture was stirred at about room temperature for about 1h. The solid obtained was filtered, washed with water and dried.
Yield: 61g (91.7%)
The crude product in ethyl acetate was heated to about 70°C to about 75°C for about 30min. The solution was cooled to about 5°C to about 10°C and stirred for about 1h. The solid obtained was filtered, washed with ethyl acetate and dried.
Yield: 54.5g; Purity: >99%

COMPARATIVE EXAMPLE 1 Preparation of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide
To a stirred mixture of 5-(4-bromophenyl)-4,6-dichloropyrimidine (5g) in dimethyl sulfoxide (40mL) was added a mixture of propane-1-sulfamide potassium salt (3.5g) in dimethyl sulfoxide (40mL) at about room temperature. The reaction mixture was stirred at about the same temperature for about 48h and saturated sodium chloride solution and hexane were added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was washed with hexane and extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine solution, concentrated under vacuum at about below 50°C and stripped out twice with methanol to give pale yellow thick oil. Yield: 4g (59.9%)

COMPARATIVE EXAMPLE 2 Preparation of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide
To a stirred mixture of 5-(4-bromophenyl)-4,6-dichloropyrimidine (20g) in dimethyl sulfoxide (100mL) was added propane-1-sulfamide potassium salt (12.13g) and potassium tert-butoxide (11.05g) at about room temperature. The reaction mixture was stirred at about the same temperature for about 1h and water and hexane were added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was washed with hexane and aqueous hydrochloric acid was slowly added to it at about room temperature to give off-white slurry. The reaction mixture was stirred at about room temperature for about 1h. The solid obtained was filtered, washed twice with water and dried. Yield: 21.2g (73.1%)

COMPARATIVE EXAMPLE 3 Preparation of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide
To a stirred mixture of 5-(4-bromophenyl)-4,6-dichloropyrimidine (5g) in dimethyl sulfoxide (25mL) was added propane-1-sulfamide potassium salt (5.79g) and potassium tert-butoxide (2.02g) at about room temperature. The reaction mixture was heated to about 50°C to about 55°C and stirred for about 1h. The reaction mixture was cooled to about room temperature and water and hexane were added to it. The reaction mixture was stirred and the two layers were separated. Aqueous hydrochloric acid was slowly added to the aqueous layer at about room temperature to give sticky oily mass. The reaction mixture was extracted twice with dichloromethane. The combined organic layer was washed with 10% aqueous sodium chloride solution, concentrated under vacuum at about below 35°C to give brown colour oily mass. Yield: 4.10g (61.6%)

EXAMPLE 2 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
A mixture of ethylene glycol (11.1g), dimethoxyethane (10mL) and potassium tert-butoxide (1.67g) was stirred at about 40°C for about 15min. A solution of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (2g) in dimethoxyethane (10mL) was added to it. The reaction mixture was heated to about 85°C to about 90°C and stirred for about 2h. The temperature of the reaction mixture was raised to about 100°C to about 105°C and the reaction mixture was stirred at about the same temperature for about 5h. The reaction mixture was cooled to about room temperature and water and aqueous hydrochloric acid were added to it. The reaction mixture was extracted thrice with ethyl acetate. The combined organic layer was concentrated under vacuum at about below 50°C to give pale yellow solid.
Yield: 1.03g (48.58%)

EXAMPLE 3 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
To a mixture of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (4g), ethylene glycol (20mL) and dimethoxyethane (20mL) was added potassium tert-butoxide (3.5g) at about room temperature. The reaction mixture was heated to about 85°C to about 90°C and stirred for about 2h. The temperature of the reaction mixture was raised to about 100°C to about 105°C and the reaction mixture was stirred at about the same temperature for about 8h. The reaction mixture was cooled to about room temperature and water and aqueous hydrochloric acid were added to it. The reaction mixture was extracted twice with ethyl acetate. The combined organic layer was concentrated under vacuum at about below 50°C and methanol (20mL) was added to the obtained residue. The reaction mixture was heated to about 50°C to about 55°C, stirred for about 15min, cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered and washed with cold methanol and dried at about 45°C to about 50°C. Yield: 2g (47.05%)

EXAMPLE 4 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
To a mixture of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (3g) in ethylene glycol (15mL) was added potassium tert-butoxide (4g). The reaction mixture was heated to about 100°C to about 105°C and stirred for about 5h. The reaction mixture was cooled to about room temperature and water, ethyl acetate and aqueous hydrochloric acid were added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C and methanol (15mL) was added to the obtained residue. The reaction mixture was heated to about 45°C to about 50°C, stirred for about 30min, cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered and washed with methanol and dried. Yield: 2.1g (66.03%)

EXAMPLE 5 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
To a mixture of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (9g) in ethylene glycol (45mL) was added potassium tert-butoxide (9.94g). The reaction mixture was heated to about 100°C to about 105°C and stirred for about 5h. The reaction mixture was cooled to about room temperature and water, ethyl acetate and aqueous hydrochloric acid were added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C and tert-butyl methyl ether (45mL) was added to the obtained residue. The reaction mixture was heated to about 40°C to about 50°C, stirred for about 30min, cooled to about 0°C to about 5°C and stirred for about 30min. The solid obtained was filtered and washed with tert-butyl methyl ether and dried at about 45°C to about 50°C. Yield: 7.1g (74.19%)

EXAMPLE 6 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
To a mixture of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (10g) in ethylene glycol (50mL) was added potassium tert-butoxide (9.7g). The reaction mixture was heated to about 110°C to about 115°C and stirred for about 5h. The reaction mixture was cooled to about room temperature and water, ethyl acetate and aqueous hydrochloric acid were added to it. The reaction mixture was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C and 2-propanol (50mL) was added to the obtained residue. The reaction mixture was heated to about 75°C to about 80°C, stirred for about 30min, cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered, washed with 2-propanol and dried at about 45°C to about 50°C.
Yield: 8.5g (79.88%)

EXAMPLE 7 Preparation of macitentan
To a stirred mixture of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (10g), toluene (100mL) and dimethyl formamide (30mL), flushed with nitrogen at about room temperature, was added sodium hydroxide (5g). The reaction mixture was stirred for about 10min and 5-bromo-2-chloropyrimidine (10g) was added to it. The reaction mixture was stirred at about room temperature for about 2h, cooled to about 20°C to about 25°C and water and ethyl acetate were added to it. Aqueous hydrochloric acid was added to the reaction mixture to adjust the pH to about 5 to about 6. The reaction mixture was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C. Methanol was added to the obtained residue and the reaction mixture was heated to about 60°C to about 65°C and stirred for about 30min. The reaction mixture was cooled to about room temperature and stirred for about 1h to give off-white slurry. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C. Yield: 10.5g

COMPARATIVE EXAMPLE 4 Preparation of macitentan
To a mixture of tetrahydrofuran (10mL) and sodium hydride (2g), flushed with nitrogen at about room temperature, was added N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (1.6g) in tetrahydrofuran (6mL). The reaction mixture was stirred for about 15min and 1.6ml dimethyl formamide (1.6mL) and 5-bromo-2-chloropyrimidine (1g) were added to it. The reaction mixture was heated to about 60°C to about 65°C and stirred for about 2h. The reaction mixture was cooled to about room temperature and 5-bromo-2-chloropyrimidine (1.5g) was added to it. The reaction mixture was heated to about 60°C to about 65°C and stirred for about 2h. The reaction mixture was cooled to about 0°C to about 5°C and methanol, aqueous hydrochloric acid and water were added to it. The reaction mixture was stirred and extracted thrice with ethyl acetate. The combined organic layer was concentrated under vacuum at about below 50°C and stripped out with methanol under vacuum at about the same temperature. Methanol was added to the obtained residue and the reaction mixture was cooled to about 0°C to about 5°C to give pale brown slurry. The solid obtained was filtered, washed with cold methanol and dried at about 45°C to about 50°C. Yield: 0.65g

COMPARATIVE EXAMPLE 5 Preparation of macitentan
A mixture of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (5g), toluene (50mL) and dimethyl formamide (10mL) was stirred to give a clear solution. The toluene was distilled out under vacuum at about below 50°C. The reaction mixture was cooled to about room temperature and toluene (50mL) and 5-bromo-2-chloropyrimidine (5.4g) were added to it. The reaction mixture was cooled to about 0°C to about 5°C and potassium tert-butoxide (6g) was added to it. The reaction mixture was stirred at about 20°C to about 25°C for about 2h to give a dark-brown colour reaction mixture and water was added to it. Aqueous hydrochloric acid (25mL) was added to the reaction mixture followed by ethyl acetate. The reaction mixture was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C. Methanol was added to the obtained residue and the reaction mixture was heated to about 45°C to about 50°C and stirred for about 30min to give pale brown slurry. The reaction mixture was cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C. Yield: 4.6g

COMPARATIVE EXAMPLE 6 Preparation of macitentan
To a stirred mixture of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (10g), toluene (150mL) and dimethyl formamide (20mL), flushed with nitrogen at about room temperature, was added potassium tert-butoxide (13.9g) and 5-bromo-2-chloropyrimidine (10.34g). The reaction mixture was stirred at about room temperature for about 30min to give a dark-brown colour reaction mixture which was cooled to about 20°C to about 25°C and water was added to it. Aqueous hydrochloric acid was added to the reaction mixture followed by ethyl acetate and activated charcoal. The reaction mixture was stirred for about 30min, filtered over hyflo bed and washed with ethyl acetate. Brownish sticky mass was observed on the hyflo bed. The filtrate was stirred and the two layers were separated. The organic layer was concentrated under vacuum at about below 50°C. Methanol was added to the obtained residue and the reaction mixture was heated to about 60°C to about 65°C and stirred for about 30min. The reaction mixture was cooled to about 25°C and stirred for about 1h to give pale brown slurry. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C. Yield: 8.5g

COMPARATIVE EXAMPLE 7 Preparation of macitentan
To a stirred mixture of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (10g), toluene (150mL) and dimethyl formamide (20mL), flushed with nitrogen at about room temperature, was added potassium tert-butoxide (14g). The reaction mixture was stirred for about 10min and 5-bromo-2-chloropyrimidine (10.8g) was added to it. The reaction mixture was stirred at about room temperature for about 30min to give a dark-brown colour reaction mixture which was cooled to about 20°C to about 25°C and water and ethyl acetate were added to it. Aqueous hydrochloric acid was added to the reaction mixture followed by activated charcoal. The reaction mixture was stirred for about 30min, filtered over hyflo bed and washed with ethyl acetate. Brownish sticky mass was observed on the hyflo bed. The filtrate was stirred and the two layers were separated. To the organic layer was added water and 5% aqueous sodium hydroxide solution till the pH is above about 7. The reaction mixture was stirred and the two layers were separated. Activated charcoal was added to the organic layer which was stirred for about 30min and filtered over hyflo bed. The filtrate was concentrated under vacuum at about below 50°C. Methanol was added to the obtained residue and the reaction mixture was heated to about 50°C to about 55°C and stirred for about 30min. The reaction mixture was cooled to about room temperature and stirred for about 1h to give pale brown slurry. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C. Yield: 7g

EXAMPLE 8
A mixture of macitentan (10g) and methanol (200mL) was heated to about 60°C to about 65°C. Activated charcoal was added to the reaction mixture which was stirred at about the same temperature for about 30min. The reaction mixture was filtered over hyflo bed and washed with hot methanol. The filtrate was cooled to about 20°C to about 25°C and stirred for about 1h. The solid obtained was filtered, washed with cold methanol and dried at about 45°C to about 50°C.
Purity: 99.93%
Ethylene glycol content: below detection limit

XRPD peaks of crystalline macitentan:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.48 13.62 3.69 24.54 3.62 6.38
7.99 11.05 20.18 25.33 3.51 88.80
11.39 7.76 85.03 25.59 3.47 12.88
13.01 6.80 41.27 26.04 3.42 7.50
13.32 6.64 9.75 26.66 3.34 18.49
13.99 6.32 15.82 27.66 3.22 7.57
14.32 6.18 12.27 28.21 3.16 23.27
16.04 5.52 100.00 28.48 3.13 34.01
17.20 5.15 13.91 29.05 3.07 5.07
18.13 4.89 46.33 29.81 2.99 2.31
18.53 4.78 49.79 31.13 2.87 36.29
19.57 4.53 7.61 32.42 2.76 4.57
20.03 4.43 23.38 32.93 2.71 7.05
20.29 4.37 8.83 33.62 2.66 3.19
21.24 4.18 18.34 34.56 2.59 3.02
21.40 4.15 18.55 35.46 2.53 3.61
22.01 4.03 30.20 36.78 2.44 3.74
22.65 3.92 10.48 37.60 2.39 6.69
22.90 3.88 21.58 38.39 2.34 4.06
23.38 3.80 38.31 39.75 2.26 4.63

EXAMPLE 9
A mixture of macitentan (10g) and methanol (200mL) was heated to about 60°C to about 65°C. Activated charcoal was added to the reaction mixture which was stirred at about the same temperature for about 30min. The reaction mixture was filtered over hyflo bed and washed with hot methanol. The filtrate was partly concentrated under vacuum at about below 50°C, then cooled to about 20°C to about 25°C and stirred for about 1h. The solid obtained was filtered, washed with cold methanol and dried at about 45°C to about 50°C.

EXAMPLE 10
A mixture of macitentan (10g) and methanol (200mL) was heated at about 60°C to about 65°C for about 30min. The reaction mixture was filtered over hyflo bed and washed with hot methanol. The filtrate was cooled to about 20°C to about 25°C and stirred for about 1h. The solid obtained was filtered, washed with cold methanol and dried at about 45°C to about 50°C.

EXAMPLE 11 Preparation of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide
To a stirred mixture of 5-(4-bromophenyl)-4,6-dichloropyrimidine (10g) in dimethyl sulfoxide (45mL) was added propane-1-sulfamide potassium salt (12.75g) in dimethyl sulfoxide at about room temperature. The reaction mixture was heated to about 50°C to about 55°C and stirred for about 3h. The reaction mixture was cooled to about room temperature and water and hexane were added to it. The reaction mixture was stirred and the two layers were separated. Aqueous hydrochloric acid was slowly added to the aqueous layer at about room temperature to give off-white slurry. The reaction mixture was stirred at about room temperature for about 2h. The solid obtained was filtered, washed with water and dried.
Yield: 13g (>90%)
The crude product in ethyl acetate was heated to about 70°C to about 75°C for about 1h. The solution was cooled to about 5°C to about 10°C and stirred for about 1h. The solid obtained was filtered, washed with ethyl acetate and dried.
Yield: 10.5g (78.9%); Purity: >99%

EXAMPLE 12 Preparation of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide
To a mixture of N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (10g) in ethylene glycol (50mL) was added potassium tert-butoxide (9.7g). The reaction mixture was heated to about 95°C to about 100°C and stirred for about 24h. The reaction mixture was cooled to about room temperature and water, methylene chloride and aqueous hydrochloric acid were added to it. The reaction mixture was stirred and the two layers were separated. The aqueous layer was extracted with methylene chloride and combined organic layer was washed with water. Organic layer was concentrated under vacuum at about below 45°C, and was stripped out with methyl tert-butyl ether. A mixture of isopropyl alcohol and methyl tert-butyl ether were added to the obtained residue. The reaction mixture was heated to about 50°C to about 55°C, stirred for about 30min, cooled to about room temperature and stirred for 30min. The solid obtained was filtered, washed with methyl tert-butyl ether and dried at about 40°C to about 45°C.
Yield: 8.5g (80.0%), Purity: >99.0%
Ethylene glycol content: below detection limit.

EXAMPLE 13 Preparation of macitentan
To a stirred mixture of N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy) pyrimidin-4-yl)propane-1-sulfamide (10g), toluene (100mL) and dimethyl formamide (20mL), flushed with nitrogen at about room temperature, sodium hydroxide (4.63g)was added. The reaction mixture was stirred for about 45min and 5-bromo-2-chloropyrimidine (11.2g) was added to it. The reaction mixture was stirred at about room temperature for about 4h, cooled to about 20°C to about 25°C and water and ethyl acetate were added to it. Aqueous hydrochloric acid was added to the reaction mixture to adjust the pH to about 4 to about 7. The reaction mixture was stirred and the two layers were separated. The aqueous layer was extracted with ethyl acetate and combined organic layer was washed with water. Activated charcoal was added to organic layer and stirred at about room temperature for about 30min and filtered over hyflo bed, and washed with ethyl acetate. Clear filtrate was concentrated under vacuum at about below 50°C, methanol was added to the obtained residue and the reaction mixture was heated to about 60°C to about 65°C and stirred for about 30min. The reaction mixture was cooled to about room temperature and stirred for about 1h to give off-white slurry. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C. Yield: 11.0g (80.8%), Purity :> 99.5%

EXAMPLE 14
A mixture of macitentan (10g) and methanol (300mL) was heated to about 60°C to about 65°C and stirred for about 30min. The reaction mixture was filtered over hyflo bed and washed with hot methanol. The filtrate was partly concentrated under vacuum at about below 50oC, then cooled to about 25°C to about 30°C and stirred for about 1h. The solid obtained was filtered, washed with methanol and dried at about 45°C to about 50°C.
Yield: 80gm, Purity: >99.5%
Ethylene glycol content: below detection limit.
,CLAIMS:WE CLAIM
1. A process for the preparation of macitentan, a compound of formula I,

the process comprising:
(a) reacting a compound of formula V with a compound of formula VI, wherein M is selected from Li, Na, K,

in the absence of a base and at a temperature in the range of about 40°C to about 150°C to give a compound of formula IV,
;
(b) reacting the compound of formula IV with ethylene glycol to give a compound of formula II,

wherein, the compound of formula II is isolated from non-ketonic solvents; and
(c) reacting the compound of formula II with a compound of formula III,

in the presence of a base selected from alkali metal hydroxides or alkaline earth metal hydroxides, to give macitentan, the compound of formula I.
2. The process of claim 1, wherein the compound of formula IV is reacted with ethylene glycol in the presence of a base.
3. The process of claim 2, wherein the base is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alcoholates, alkaline earth metal alcoholates, alkali metal hydrides.
4. The process of claim 1, wherein the non-ketonic solvents are selected from the group consisting of alcohols, ethers, esters, nitriles, hydrocarbons, haloalkanes, or mixtures thereof.
5. The process of claim 4, wherein the non-ketonic solvents are isopropyl alcohol, tert-butyl methyl ether or mixture thereof.
6. The process of claim 1, wherein the compound of formula II is obtained with ethylene glycol content in the range of about 15 ppm to about 30 ppm.
7. The process of claim 1, wherein the compound of formula II is reacted with the compound of formula III in the presence of sodium hydroxide.