Claims:We Claim:
1) A process for the preparation of Macitentan (I)

(I)
comprising the steps of:
a) reacting 5-(4-bromophenyl)-4,6-dichloropyrimidine (II) with a potassium salt of N-propyl sulfamide (III), which was prepared in-situ to yield N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (IV);

b) reacting N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (IV) with ethylene glycol acting as reactant cum solvent to yield N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (V);

c) reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (V) with 5-bromo-2-chloropyrimidine (VI) in presence of non-polar solvent to yield Macitentan(I); and/or

d) optionally purifying Macitentan to obtain substantially pure Macitentan having a purity of greater than 99.5%.

2) A process for the preparation of Macitentan according to claim 1, wherein substantially pure and having purity of greater than 99.5% (By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.

Impurity-A
Impurity-B

Impurity-C
Impurity-D

3) A process for the preparation of Macitentanaccording to claim 1, wherein potassium salt of N-propyl sulfamide was prepared by reacting N-propyl sulfamide with potassium tertiary butoxide, potassium carbonate, potassium hydride

4) A process for the preparation ofMacitentan according to claim 1, wherein reaction between N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (IV) and ethylene glycol has been carried out at a temperature ranging between 90 and 110°C.

5) A process for the preparation of Macitentan according to claim 1, wherein non-polar solvent used in step-c) is selected from toluene, xylene, n-hexane, n-heptane or mixtures thereof

6) A process for the preparation of Macitentan according to claim 1, wherein 5-bromo-2-chloropyrimidine is added in step-c) after dissolving in amide solvent selected from such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, dimethyl sulfoxide or mixtures thereof

7) A process for the preparation of substantially pure Macitentan according to claim 1, wherein step d) of purifying Macitentancomprises the steps of:
a) dissolving Macitentan in a polar solvent;
b) heated to reflux;
c) optionally adding precipitating solvent; and
d) precipitated/recrystallized solid was washed with solvent to obtain pure Macitentan.

8) A process for the purification of Macitentan (I) according to claim 6, wherein polar solvent is selected from polar solvent selected from nitrile solvents such as acetonitrile, propionitrile; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol, tertiary butanol, n-butanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof and precipitating solvent selected from water, dimethylcarbamate

9) Substantially pure Macitentan having purity of greater than 99.5% (By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.

Impurity-A
Impurity-B

Impurity-C
Impurity-D

10) A pharmaceutical composition comprising substantially pure Macitentan having purity of greater than 99.5% (By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.

Dated this 4thday of May 2016 Signature:
Dr. A.K.CHATURVEDI

, Description:FIELD OF THE INVENTION
The present invention relates to aprocess for the preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentan of Formula (I).

(I)
BACKGROUND OF THE INVENTION
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentanis an endothelin receptor antagonist. Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of Macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.

Macitentanwas approved by USFDA in 2013 and is marketed under the brand name OPSUMIT®, is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced hospitalization for PAH.

Macitentanwas chemically known as N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I).

Macitentan is a crystalline powder with the empirical formula C19H20Br2N6O4S and a molecular weight of 588.27.Macitentan is achiral and insoluble in water. In the solid state Macitentan is very stable, is not hygroscopic, and is not light sensitive.

As per EMEA “Several polymorphic forms have been described including different solvates. All Macitentan batches manufactured so far for clinical studies and commercial purposes correspond to the same stable polymorphic form which is a true polymorph with a melting point of 135°C. It is the thermodynamically most stable form at room temperature. Long-term stability studies on several clinical and registration batches showed no polymorphic change of Macitentan after up to 36 months of storage at 30 °C / 65% RH. Results of the dynamic vapor sorption of Macitentan show that it is not hygroscopic”

Macitentan is generically and specifically claimed in US7094781 B2. This patent disclosed a generalized process for the preparation of Macitentan and its analogs. Macitentan was generically disclosed in Formula I-V of this patent. Further, this patent also disclosed active metabolites of Macitentan as disclosed in US 8324232, which is shown below:

Bolli et al in Journal of Medicinal Chemistry 2012, 55, 7849-7861disclose a process for the preparation of Macitentan starting from 5-(4-Bromophenyl)-4,6-dichloropyridine, which is similar to the process as disclosed in US ‘781. The process is as demonstrated in Scheme-I:
Scheme-I

US 8324232 disclosean active metabolite of Macitentan. As described above US ‘781 generically disclosed the active metabolites of Macitentan. The person skilled in the art will know how to prepare this active metabolite of Macitentan using the process as disclosed in US ‘781.

IPCOM000235526 published on March 06, 2014 disclosed crystalline Macitentan. IPCOM00236886 published on May 21, 2014 disclosed crystalline Form-A, Form-B and amorphous form of Macitentan.

WO 2014173805 discloses crystalline Form –I of Macitentan. This patent disclosed that the crystalline Form-I of Macitentan was obtained as per Journal of Medicinal Chemistry 2012 by crystallization using methanol solvent.

WO 2014198178 disclosed crystalline Form II of Macitentan and a process for the preparation of Form II of Macitentan.

WO2016009322 discloses crystalline Form-III, Form-IV, Form-V and amorphous forms of Macitentan.

EP2907811discloses a process for the preparation ofMacitentan. The process disclosed in EP ‘811is as disclosed below:
Scheme-II:

WO2014155304 discloses a process for the preparation of Macitentan. The process disclosed in WO ‘304 is as disclosed below:

WO2015004265 discloses a process for the preparation of Macitentan. The process disclosed in WO ‘265 is as disclosed below:

The present inventors has repeated the above process and found the following disadvantages:
? No efficient scalable process has been disclosed in the literature. The use of unstable salts may yields in the formation of impurities, which requires several purification steps to yield highly pure Macitentan, which meets the requirements of ICH guidelines.
? Unwanted reactions are observed during the formation of Macitentan, due to the involvement time lagging process.
? Incomplete reactions were observed with excessive impurity formation due to incomplete conversion.
? Highly flammable solvents are used in the preparation of Macitentan, which are not feasible

In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of Macitentan, using industrially viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.

OBJECTIVE OF THE INVENTION
The main objective of the invention relates to aprocess for the preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentan(I).

Yet another objective of the invention relates to a process for the preparation of substantially pure N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentan (I)

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Macitentan (I)

(I)
comprising the steps of:
a) reacting 5-(4-bromophenyl)-4,6-dichloropyrimidine (II) with a potassium salt of N-propyl sulfamide (III), which was prepared insitu to yield N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (IV);

b) reacting N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (IV) with ethylene glycol acting as reactant cum solvent to yield N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (V);

c) reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl sulfamide (V) with 5-bromo-2-chloropyrimidine (VI) in presence of non-polar solvent to yield Macitentan; and

d) optionally purifying Macitentan to obtain substantially pure Macitentan having a purity of greater than 99.5%.

The present invention further relates substantially pure Macitentan having purity of greater than 99.5% (By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.

Impurity-A

Impurity-B

Impurity-C

Impurity-D

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystallineN-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentanobtained according to the process of the present invention.
Fig. 2 is an example of Differential Scanning Calorimetry(“DSC”) pattern of crystallineN-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentanobtained according to the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Macitentan (I)comprising preparing potassium salt of N-propyl sulfamide (III), which was prepared in-situ comprises of dissolving N-Propyl-sulfamide in a solvent selected from Dimethyl sulfoxide, Dimethyl acetamide, dimethyl formamide, N-Methyl pyrrolidine, 1,4-dioxane, tetrahydrofuran; and then adding a potassium source selected from potassium tertiary butoxide, potassium carbonate, potassium hydride. To the obtained reaction mass, 5-(4-bromophenyl)-4,6-dichloropyrimidine (II)was added directly (or in solution form with an organic solvent) and stirred the reactionmassfor 5-6 hours at a temperature ranging between 25-30°C. Water was added slowly in to the reaction mass and stirredthe solution. To the obtained reaction mass citric acid solution was added slowly for an about 1-2 hrs to obtain solid. The precipitated solid was filtered and washed with water and suck dried the material for 30 min. The product was dried under vacuum at 50-55°C for 10-12 hrs to obtain N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide.

The prior art process also involves the condensation potassium salt of N-propyl sulfamide with 5-(4-bromophenyl)-4,6-dichloropyrimidine. However, the present inventors found that these prior art process requires 48 hours for completion of the reaction, which is not industrially feasible and yields in the formation of impurities and by products in the final Macitentan and quality of Macitentan obtained by the prior art process not meeting the ICH guidelines.
In view of the above, to overcome the above disadvantages, the present inventors surprisingly found that the condensation of 5-(4-bromophenyl)-4,6-dichloropyrimidine with potassium salt of N-propyl sulfamide, which was formed in-situ completes the reaction within 5 to 6 hours, which is industrially viable. Further, the product obtained as per the process meets the quality of ICH guidelines.

The above obtained N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propyl sulfamide was added slowly to a Potassium tert-butoxide solution in Ethylene glycol at 10-15 °C and stirred the solution for 30 min to 1 hour at 25-30°C. The contents of the reaction mass were raised to 90-130°C for about 12-14 hrs. The obtained reaction mass was cooled to room temperature and then water and methanol was added. Reaction mixture was cooled to 15-20 °C and added Citric acid solution for a period of about 1 hour to 2 hours and the reaction mass was maintained for 2-3 hrs at room temperature. Filter the solid and washed with water, suck dried the material for 30 min. The product was dried under vacuum at 50-55 °C for 20-24 hrs to obtain N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl sulfamide.

The prior art process also involves the condensation N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide with ethylene glycol in presence of a 1,2-dimethoxyethane solvent. The present inventors found that these prior art process requires 70 hours for completion of the reaction, which is not industrially feasible and yields in the formation of impurities and by products in the final Macitentan and quality not meeting the ICH guidelines.Further, these processes involve cumbersome workup to remove the impurities.

In view of the above, the present inventors surprisingly found that the use of ethylene glycol as a reactant and as a solvent not only completes the reaction in 12 hours. But also, yield in highly pure N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide, which does not involves extra purification. The process developed by the present inventors is industrially feasible and yields in highly pure Macitentan.

The above obtained N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide was dissolved in a non-polar solvent selected from toluene, xylene, n-hexane, n-heptane or mixtures thereof. To the obtained solution sodium hydride was added slowly at 10-15°C and the stirred the contents for 20 minutes to 1 hour at 10-15°C. To the obtained reaction mass 5-bromo-2-chloropyrimidinesolution was added slowly, which was prepared by dissolving in amide solvent selected from such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide or mixtures thereof. The reaction mixture was allowed to room temperature and stirred for 5-6 hrs. Citric acid solution was added slowly at 10-15 °C and allowed the reaction mixture to obtaina temperature of around 25-30ºC and filter the reaction mass through Celite bed. The organic layer was separated and washed with sodium chloride solution. The organic layer was separated and distilled out under vacuum at 60-65 °C to obtain residue. Methanol was added to the residue and stirred for about 1 hr at temperature ranging between 10-15 °C to obtain solid. The precipitated solid was filtered and washed with chilled methanol and suck dried for 30 min. The solid was dried under vacuum at 55-60°C for 20-24 hrs to obtain Macitentan.

Sodium hydride is commercially available in the mineral oil (wherein 55-60 % sodium hydride and 40-45% mineral oil). The prior art process involves removal of mineral oil by washing with hexane to increase the reactivity of sodium hydride, which is very difficult to handle in the industrial scale due to highly explosiveness and quickly catches fire in air.

In view of the above the present inventors developed a process, which is safe and industrially feasible by directly using commercially available 55-60% sodium hydride. However, the present inventors surprisingly found that the use of non-polar solvent in combination with formamide solvent completes the reaction within 5-6 hours without any difficulty.

The obtained Macitentan was purified to obtain substantially pure Macitentan comprising the steps of:
a) dissolving Macitentan in a polar solvent;
b) heated to reflux;
c) optionally adding precipitating solvent; and
d) precipitated/recrystallized solid was washed with solvent to obtain pure Macitentan.

The obtained Macitentan was purified using a polar solvent selected from selected from nitrile solvents such as acetonitrile, propionitrile; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol, n-butanol, tert-butanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof; at a temperature ranging from 60-90°C, by stirring the reaction mixture for 15 to 45 minutes to get clear solution, cooling to 50-60°C and then crystallizing at room temperature or adding precipitating solvent selected from water ordimethylcarbonate;was added slowly for 30 minutes. The solid precipitates out and the obtained solid was filtered, washed with polar / non-polar solvent to yield pure Macitentan.The obtained Macitentan was purified using column chromatography using polar/non-polar solvents to yield pure Macitentan.If the desired purity is not achieved, it is recommended to perform the same purification process operation by using same/different solvent as disclosed above to obtain the substantially pure Macitentan having a purity of greater than 99.5%.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Macitentan. N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentan obtained according to the present invention is having purity greater than 99.5%.

The obtained pure N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]-N'propylsulfamide(I) or Macitentan having purity greater than 99.5% and substantially free from process related impurities and meets the requirement of ICH guidelines.
Macitentanobtained according to the present invention is having purity of greater than 99.5% and substantially free from process related impurities. Macitentanobtained according to the present invention is analyzed by PXRD and obtained PXRD pattern appears to be crystalline.

The process related impurities that appear in the impurity profile of the N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanmay be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

In another embodiment, the present invention relates to a substantially pure Macitentan having a purity of greater than 99.5 %(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.5% by HPLC.

Impurity-A

Impurity-B

Impurity-C

Impurity-D

In another embodiment, the present invention relates to a substantially pure Macitentan having a purity of greater than 99.6%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.4% by HPLC.

In another embodiment, the present invention relates to a substantially pure Macitentan having a purity of greater than 99.7%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.3% by HPLC.

In another embodiment, the present invention relates to a substantially pure Macitentan having a purity of greater than 99.8%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.2% by HPLC.

In another embodiment, the present invention relates to a substantially pure Macitentan having a purity of greater than 99.9%(By HPLC) and total impurities A to D and unknown impurities collectively less than 0.1% by HPLC.

In another embodiment, the N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanobtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanobtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (I) or Macitentanof the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example 1
Preparation of N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide:
Potassium tert-butoxide(90 gm, 0.802 mol) was added in to a reaction flask containing a solution of N-Propyl-sulfamide (N-Propyl-sulfamide (82 gm, 0.593 mol) in DMSO (250 ml)) and stirred the reaction mass at room temperature for 30 min to obtain potassium salt of N-propyl sulfamide. 5-(4-bromophenyl)-4,6-dichloropyrimidine (100 gm, 0.329 mol) was added in to the reaction mass and stirred the contents for 5-6 hrs at 25-30°C. DM water (500 ml) was added to the reaction mass a stirred solution. Further 10% citric acid solution (500 ml) was added slowly for an about 1-2 hrs to obtain solid. The precipitated solid was filtered and washed with DM water (120 ml) and suck dried the material for 30 min. The product was dried under vacuum at 50-55 °C for 10-12 hrs to obtain title product.
Yield: 137 gm
Purity (By HPLC): 92.0%

Example 2
Preparation of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl sulfamide:
Potassium tert-butoxide (560.0 gm, 4.991 mol) was added in to a reaction flask containing ethylene glycol (3.5 lit) at 10-15 °C and stirred the solution for 30 min at 25-30 °C. N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (350.0 gm, 0.863 mol) was added slowly in to the reaction mass and the contents was heated to 100-105 °C for 12-14 hrs. The obtained reaction mass was cooled to room temperature and then DM water (700 ml) and methanol (175.0 ml) was added. Reaction mixture was cooled to 15-20 °C and added 20% Citric acid solution (4.5 lit) for a period of about 1 hour to 2 hours and the reaction mass was maintained for 2-3 hrs at room temperature. Filter the solid and washed with water (700.0 ml), suck dried the material for 30 min. The product was dried under vacuum at 50-55 °C for 20-24 hrs to obtain title product.
Yield: 236 gm
Purity (By HPLC): 92.04%

Example 3
Preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide (Macitentan).
Sodium hydride (23.80 gm, 0.992 mol) was added in to a reaction flask containing solution of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (34.0 gm, 0.079 mol) in Toluene (680.0 ml), at 10-15°C. The obtained reaction mass was stirred for 20-30 mins at 10-15 °C. 5-bromo-2-chloropyrimidinesolution(5-bromo-2-chloropyrimidine (62.0 gm, 0.321 mol) in DMF (136.0 ml)) was added slowly to the reaction mixture at 10-15 °C. The reaction mixture was allowed to room temperature and stirred for 5-6 hrs. 10% citric acid solution (1020.0 ml) was added at 10-15 °C and allow the reaction mixture at 25-30ºC and filter the reaction mass through Celite bed. The organic layer was separated and washed with 10% NaCl solution (170 ml). The organic layer was separated and distilled out under vacuum at 60-65 °C to obtain residue. Methanol (68.0 ml) was added to the residue and stirred for 1 hr at 10-15 °C to obtain solid. The precipitated solid was filtered and washed with chilled methanol (10 ml) and suck dried for 30 min. The solid was dried under vacuum at 55-60°C for 20-24 hrs to obtain title product.
Yield: 31.1gm
Purity (By HPLC): 97.32 %

Example 4
Purification ofMacitentan
Macitentan (142.0 gm) was charged into a reaction flask containing Acetonitrile (1420.0 ml) and heated to 70-75 °C for 15 min to get clear solution, the reaction mixture was cooled to 50-55 °C and DM water (1420.0 ml) was added in 30 min. The reaction mixture was allowed to cool to room temperature and stirred for 1 hr to obtain solid. The precipitated solid was filtered and washed with water (284 ml) to yield pure Macitentan.
Yield: 145.0 gm
Purity (By HPLC): 99.29%

Example 5
Purification ofMacitentan
Macitentan (80.0 gm) was charged into a reaction flask containing Acetonitrile (640.0 ml) and heated to 70-75 °C for 15 min to get clear solution, the reaction mixture was cooled to 50-55 °C and DM water (640.0 ml) was added in 30 min. The reaction mixture was allowed to cool to room temperature and stirred for 1 hr to obtain solid. The precipitated solid was filtered and washed with water (160.0 ml). The product was dried under vacuum for 24 hrs at 55-60 °C to obtain pure Macitentan.
Yield: 71.6 gm
Purity (By HPLC): 99.72%

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.