DESC:FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of substantially pure macitentan and to macitentan prepared from such a process.

BACKGROUND OF THE INVENTION:
Macitentan of Formula (I),

(I)

chemically named as N-[5-(4-bromophenyl)-6-[2-[5-bromo-2-pyrimidinyl)oxy]ethoxy]-4pyrimidinyl]-N’-propylsulfamide, is an endothelin receptor antagonist. Macitentan is marketed under the trade name Opsumit® and is indicated (as monotherapy or in combination) for the long term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class II to III. Opsumit® is taken orally in tablet form at a dose of 10 mg once daily, with or without food.

WO02053557 A1 discloses a process for the preparation of macitentan as shown in Scheme 1:

Scheme 1

wherein in step 1 of the process, the compound of formula (III) is reacted with ethylene glycol using potassium tertbutoxide in dimethoxyethane at 100 oC. The isolated solid is further purified by column chromatography, yielding the compound of formula (II). In step 2, the compound of formula (II) is added to sodium hydride (NaH) in tetrahydrofuran (THF), diluted with dimethylformamide (DMF), and then reacted with 5-bromo-2-chloropyridine at 60 oC to obtain macitentan of formula (I). The compound of formula (I) is further crystallized according to the disclosed method.

Bolli et.al., J. Med. Chem., (2012), 55, 7849-7861, describes an alternative route for step 1 of Scheme 1, wherein the compound of formula (III), is reacted with excess ethylene glycol in the presence of a large quantity of base, such as potassium tert-butoxide (3-4 equivalents), at a high temperature such as 100oC for 70hrs to obtain the compound of formula (II). Ethylene glycol is toxic in nature and is a high boiling solvent, rendering it difficult to use on industrial scale and difficult to remove by distillation.

WO2015004265 discloses preparation of the intermediate compound of formula (II), N-[5-(4-bromophenyl)-6-(2hydroxyethoxy)-4-pyrimidinyl]-N'-propyl-sulfamide, or a salt thereof (Scheme 1) in the presence of ethylene glycol and a base, which process comprises extracting the compound of formula (II) using methyl iso-butyl ketone (MIBK) as the solvent. However, it has been observed that MIBK is a hazardous solvent and prolonged contact with MIBK has also shown many adverse health effects on humans.

WO2014155304 discloses a process for preparing macitentan as shown in Scheme 2 wherein the compound of formula (III) is reacted with 2-(t-butoxy)ethanol to yield the compound of formula (IIIA), which is selectively deprotected to yield the compound of formula (II). The compound of formula (II) is further reacted with 5-bromo-2-chloropyridine to obtain macitentan of formula (I).

It has been seen from the prior art mentioned above, that the method of synthesising macitentan in a sufficient purity needs numerous purification steps in order to remove impurities formed during the process. Owing to these drawbacks, there is a continuing need to develop an easy, efficient, economical and industrially viable process for the synthesis of macitentan.

Therefore, there is a need to develop an improved, commercially viable and environmentally friendly process for preparing macitentan with high yield and purity using non-hazardous conditions and easy to handle reagents and solvents.

OBJECTIVES OF THE INVENTION:
The principal object of the present invention is to provide a process for the preparation of macitentan using a green chemistry approach, thereby using a green solvent that is environmentally friendly.

Another object of the invention is to provide a process for the preparation of substantially pure macitentan in high yield.

Yet another object of the present invention is to provide a process for the preparation of macitentan which is simple, economical and suitable for industrial scale up.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for preparing macitentan of formula (I):

(I)

by reacting a compound of formula (II):

(II)

with 5-bromo-2-chloro pyrimidine in the presence of a suitable base and a suitable polar aprotic solvent selected from the group comprising 2-methyltetrahydrofuran, dialkylcarbonate (such as dimethylcarbonate or diethylcarbonate) and the like, to obtain a compound of formula (I); and optionally thereafter purifying the compound so formed.
In a further aspect, the present invention provides a process for preparing macitentan of formula (I):

(I)

comprising the following steps:
i) reacting a sulfamide compound of formula (III):

with ethylene glycol in the presence of a suitable base to obtain a compound of formula (II):

;
(II)

reacting a compound of formula (II) with 5-bromo-2-chloro pyrimidine in the presence of a suitable base and a polar aprotic solvent selected from the group comprising 2-methyltetrahydrofuran, dialkylcarbonate (such as dimethylcarbonate or diethylcarbonate) and the like, to obtain a compound of formula (I); and optionally thereafter purifying the compound so formed.

Advantageously, macitentan prepared according to the process of the present invention is in substantially pure form and may be used without further purification.

Optionally, steps (i) and (ii) as hereinbefore described are carried out without isolation of the intermediate compound of formula (II) in a one pot synthesis to obtain a compound of formula (I). In other words, in one aspect of the present invention, intermediate compound of formula (II) is not isolated from the reaction mixture as a solid.

The present invention also provides a one-pot process for preparing macitentan of formula (I):

(I)

comprising the following steps:
a) reacting a compound of formula (III):

with ethylene glycol in the presence of a suitable base to obtain a compound of formula (II):

(II);

b) adding one or more suitable polar aprotic solvents selected from the group comprising of 2-methyltetrahydrofuran, dialkylcarbonate and the like, and water, stepwise or simultaneously, to the resulting reaction mixture to form an organic layer and an aqueous layer;
c) separating the organic layer so formed;
d) adding a suitable base and 5-bromo-2-chloropyrimidine to the resulting organic layer to obtain a compound of formula (I);
e) isolating the compound of formula (I); and f) optionally, purifying the compound so formed.

Preferably, the polar aprotic solvent is selected from 2-methyltetrahydrofuran, dimethylcarbonate, diethylcarbonate and the like.

DETAILED DESCRIPTION OF THE INVENTION:
Nowadays with increasing ecological problems like pollution, global warming etc., the emphasis in industries is not only on economical processes but also on green processes that minimize the use and generation of hazardous substances. Thus, in present circumstances, there has become a need to combine economic and ecological principles in any process development. Accordingly, these objects are accomplished by the present invention, which in its broadest aspects provides a green process for preparation of “substantially pure macitentan” without utilizing hazardous solvents as well as high capital intensive processes. The inventors of the present invention have rationally designed an improved process for preparation of macitentan using a green solvent, making the process eco-friendly, inexpensive and industrially viable. These green solvents are alternatives to dichloromethane and tetrahydrofuran. Also the product obtained is in high yield and high purity without involving tedious and costly purification processes like column chromatography.

The present invention relates to the synthesis of macitentan and employs “green” (i.e. non-toxic) polar aprotic solvents such as 2-methyl THF (2-methyltetrahydrofuran), dialkylcarbonates, including but not limited to dimethylcarbonate and diethylcarbonate and the like, which contribute to green chemistry. The use of 2-methyl THF, which is environmentally friendly and safe, rather than THF, as reported in the prior art, reduces the reaction times and also yields macitentan in high purity.

The present invention also provides a process for obtaining substantially pure macitentan of formula (I). The inventors of the present invention observed that macitentan obtained using the process disclosed in the prior art process (WO 2002053557) is 62.52% pure whereas the processes of the present invention described herein advantageously yield macitentan having purity at least about 99.5% as depicted in below Table 1.

Impurity WO 2002053557 Present invention


5-Bromo-2-chloro pyrimidine

Not detected

Not detected


Hydroxy Compound (II)



21.32%



0.01%

Sulfamide compound (III)


0.71%


Not detected

5-(4-bromophenyl)-4,6dichloropyrimidine


Not detected


0.01%
Unspecified impurity 4.63% 0.03%
Total impurities 34.74% 0.10%
Purity 65.26% 99.90%

Table 1
The present invention describes a practical, economical and efficient synthesis for the preparation of macitentan. This process is particularly advantageous in comparison with known methods because the reaction may be carried out according to a “one-pot” method, i.e. without isolating the intermediates formed. The process of the present invention eliminates the risk of handling hazardous chemicals, the enhanced cost associated with multiple reactors, and it reduces the reaction time and clean-up, thus making the process more industrially viable.
According to the present invention, there is provided an improved process for the synthesis of macitentan as depicted below in reaction Scheme 3:

Scheme 3

As used herein, the term “sulfamide compound of formula (III)” refers to the compound N-[5-(4-bromophenyl)-6-chloro-4-pyrimidinyl]-N'-propyl-sulfamide:

.

As used herein, the term “hydroxy compound of formula (II)” refers to the compound N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-propyl- sulfamide:

(II).

As used herein, the terms “substantially pure” and “high purity” refer to macitentan having a purity (measured by HPLC) of at least 99.5%, preferably above about 99.7% and more preferably above about 99. 90%.

As used herein, the terms “Green chemistry”, “Green solvent” and “Green approach” refer to a philosophy of chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances. Examples of suitable “green” solvents which may be employed in the process of the present invention include, but are not limited to, 2-methyltetrahydrofuran, dialkylcarbonates such as dimethylcarbonate and diethylcarbonate and the like.

In one aspect, according to step (i) of the process of the present invention, the sulfamide compound of formula (III) is reacted with ethylene glycol in presence of a suitable base, to give the hydroxy compound of formula (II).

Suitable bases for use in step (i) of the process of the present invention include, but not limited to, an organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3) and the like, or any combination thereof. Preferably, the base is sodium hydroxide.

In one aspect, according to step (i) of the process of the present invention, the molar ratio of ethylene glycol to sulfamide compound of formula (III) is suitably in the range of from 1-10:1, i.e. from 1 to 10 equivalents of ethylene glycol per equivalent of sulfamide compound of formula (III). Preferably, the molar ratio is from 6:1, i.e. 6 equivalents of ethylene glycol to one equivalent of sulfamide compound of formula (III).

Step (i) of the process of the present invention is optionally carried out in a suitable solvent. Examples of suitable solvents include, but are not limited to, polar aprotic solvents, such as 2-methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate, or any combination thereof. Preferably, the solvent is 2-methyltetrahydrofuran.

According to step (i) of the process of the present invention, the reaction mass (mixture) formed upon treatment of the sulfamide compound of formula (III) with ethylene glycol in presence of a suitable base is optionally stirred at a temperature ranging from about room (ambient) temperature to about the reflux temperature of solvent used. Suitably, the reaction mass is heated at a temperature in the range from about 20 ?C to about 120 ?C.

After formation of the hydroxy compound of formula (II) is complete, the reaction mixture is typically cooled and further quenched using 1N HCl. Preferably, water is also added. The reaction mass is optionally further extracted with a suitable solvent, such as a polar aprotic solvent. Examples of suitable solvents include, but are not limited to, 2-methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate, and the like. Preferably, the solvent is 2-methyltetrahydrofuran.

According to step (i) of the present invention, the hydroxy compound of formula (II) is optionally purified using one or more suitable solvents including, but not limited to, C1-C4 alcohols, esters such as ethyl acetate, ketones such as acetone, hydrocarbons such as toluene, xylene, heptane and the like or any combination thereof. Preferably, purification of the hydroxy compound of formula (II) is carried out using a mixture of methanol and toluene, such as 5% methanol in toluene.

In one aspect, according to step (ii) of the process of the present invention, the hydroxy compound of formula (II) is reacted with 5-bromo-2-chloropyrimidine in the presence of a suitable base and an aprotic solvent to obtain macitentan of formula (I).

Suitable aprotic solvents for use in step (ii) of the process of the present invention include, but are not limited to, 2-methyltetrahydrofuran, dialkylcarbonates, such as dimethylcarbonate and diethylcarbonate and the like, or any combination thereof. Preferably, the solvent is 2-methyltetrahydrofuran.

Suitable bases for use in step (ii) of the process of the present invention include, but are not limited to, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide and the like. Preferably, the base is sodium tert-butoxide.

According to step (ii) of the process of the present invention, the compound of formula (I) so formed is optionally purified using one or more suitable solvents including, but not limited to, organic solvents such as C1-C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like, or any combination thereof. Preferably, the purification solvent is ethyl acetate.

In accordance with the process of the present invention, steps (i) and (ii) may optionally be carried out in a “one-pot” synthesis to obtain a compound of formula (I), comprising the steps of:
a) reacting the compound of formula (III) with ethylene glycol in presence of a suitable base;
b) extracting the compound of formula (II) obtained in step (a) in a mixture of one or more suitable polar aprotic solvents selected from the group comprising of 2-methyltetrahydrofuran, dialkylcarbonate and the like;
c) adding a suitable base and 5-bromo-2-chloropyrimidine to the resulting organic layer; and
d) isolating and purifying the compound of formula (I) so formed in one or more suitable solvents.

Suitable bases for use in step a) of the one-pot process of the present invention include, but not limited to, organic bases, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or inorganic bases, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3) and the like. Preferably, the base is sodium hydroxide.

According to step a) of the one-pot process of the present invention, the molar ratio of ethylene glycol to sulfamide compound of formula (III) is suitably in the range of from 1-10:1, i.e. from 1 to 10 equivalents of ethylene glycol per equivalent of sulfamide compound of formula (III). Preferably, the molar ratio is from 6:1, i.e. 6 equivalents of ethylene glycol to one equivalent of sulfamide compound of formula (III).
Step a) of the one-pot process of the present invention is optionally carried out in a suitable solvent. Examples of suitable solvents include, but are not limited to polar aprotic solvents, such as 2-methyltetrahydrofuran, dialkylcarbonates and the like, or any combination thereof. Preferably, the solvent is 2-methyltetrahydrofuran.

According to step a) of the one-pot process of the present invention, the reaction mass (mixture) formed upon treatment of the sulfamide compound of formula (III) with ethylene glycol in presence of a suitable base is optionally stirred at a temperature ranging from about room (ambient) temperature to about the reflux temperature of solvent used. Suitably, the reaction mass is heated at a temperature in the range from about 20 ?C to about 120 ?C.

After formation of the hydroxy compound of formula (II) is complete, the reaction mixture is typically cooled and further quenched using 1N HCl. Preferably, water is also added. The reaction mass is optionally further extracted using one or more suitable solvents, treated with water and dried. A suitable drying agent is sodium sulphate.

Suitable solvents include, but are not limited to, organic solvents, such as polar aprotic solvents, including 2-methyltetrahydrofuran, dialkylcarbonates and the like. Preferably, the solvent is 2-methyltetrahydrofuran.

The compound of formula (II) obtained in step a) of the one-pot process of the present invention is extracted using a mixture of one or more suitable organic solvents and one or more suitable aqueous solvents. The organic layer is preferably cooled to a temperature between about 5 °C to 0 °C, preferably 3 ± 2 °C, and subjected to lotwise (dropwise) addition of suitable base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide and the like.

5-bromo-2-chloropyrimidine is added to the resulting mixture along with one or more suitable solvents including, but not limited to, one or more suitable polar aprotic solvents, such as 2-methyltetrahydrofuran, dialkylcarbonates and the like. Preferably, the solvent is 2-methyltetrahydrofuran.

Preferably, the temperature of the reaction mass is subsequently raised to about room (ambient) temperature and maintained at such temperature for about 3-4 hours.

According to step d) of the one-pot process of the present invention, the compound of formula (I) is purified using one or more suitable solvents including, but not limited to, organic solvents such as C1-C4 alcohols, esters such as ethyl acetate, ketones such as acetone and the like. Preferably, the purification solvent is ethyl acetate.

Macitentan obtained by present the process of the present invention advantageously has a purity (measured by HPLC) of at least 99.5%, preferably above about 99.7% and more preferably above about 99.90%. In accordance with the present invention, there is provided macitentan having a chemical purity (measured by HPLC) of at least 99.5%, preferably above about 99.7% and more preferably above about 99. 90%.

The present invention further provides a pharmaceutical composition comprising macitentan prepared in accordance with a process described herein and one or more pharmaceutically acceptable excipients.

The sulfamide compound of formula (III) may be prepared by reacting 5-(4-bromophenyl)-4,6-dichloropyrimidine with an alkaline metal salt of N-propyl sulfomyl amide in accordance with known methods or by any other process known in the art.

The details of the invention provided in the following examples are given by way of illustration only and should not be construed to limit the scope of the present invention.

EXAMPLES:

Example: 1
Preparative Example: Preparation of sulfamide (III)
600 ml of DMSO was added to 6.4 g of Sodium hydroxide, 100 g of reacting 5-(4-bromophenyl)-4,6dichloropyrimidine, followed by 116 g of N-propyl sulfomyl amide potassium salt (Sodium salt can also be used). The reaction mixture was stirred at 40±5 °C for 6 hrs. On completion of the reaction, the reaction mass was cooled to 27±2 °C and 1000 ml of purified water was added. The pH was adjusted with 1N HCl solution, followed by filtration. Wet cake was further treated with purified water and heated at 50±2 ºC for 30 minutes, cooled at 27±2 ºC. The solid was filtered, washed with purified water. The water slurry wet material was further subjected to methanol purification, heated at 50±2 ºC for 30 mins, cooled at 27±2 ºC. The final solid obtained was washed with methanol and dried under vacuum at 43±2 ºC for 12 hours.
Dry weight: 115g

Example: 2
Preparation of hydroxyl compound (II):
600 ml of ethylene glycol was added to 39.5 g of sodium hydroxide followed by 100 g of sulfamide (III), maintaining the reaction temperature at 27±2 °C. The reaction mass was heated to 108±2 °C and maintained at that temperature for 6 hours. On completion of the reaction (checked by TLC), the reaction mass was cooled to 27±2 ºC and 1000 ml of 2-methyl THF was added, followed by 1000 ml of purified water. The pH of the resulting solution was adjusted to 2-3 using 1N HCl at 20 °C. The organic layer was separated and the further aqueous layer was extracted with 300 ml of 2-methyl THF. Combined 2-methyl THF layers were dried over sodium sulphate and further distilled under vacuum. To the resulting residue was added 400 ml of 5% methanol in toluene and the solution was heated to 63±2 ºC. The solution was cooled to 27±2 ºC, further chilled to 3±2 °C, filtered, washed with toluene and dried under vacuum at 63±2 C for 12 hours.
Dry weight: 85 g.

Example: 3
Preparation of hydroxyl compound (II):
600 ml of ethylene glycol was added to 39.5gm of sodium hydroxide followed by 100 g of sulfamide compound (III) maintaining temperature 27±2°C. The reaction mass was heated at 108±2°C and maintained for 6 hours. On completion of reaction (checked by TLC), reaction mass was cooled to 27±2ºC and 600 ml of purified water was charged followed by pH adjustment to 6.0 to 7.0 with 1N HCl. Solution was heated to 55±2ºC and stirred for 30 minutes, further cooled to 27±2ºC, filtered and dried. To the dried material was added 400 ml of 5% methanol in toluene and the solution was heated at 63±2ºC. The solution was cooled at 27±2ºC, further chilled to 3±2°C, filtered, washed with toluene and dried under vacuum at 63±2°C for 12 hours.
Dry weight: 90 g.

Example: 4
Preparation of Macitentan (I):
A solution of 1000 ml of 2-methyl THF and 100 g of hydroxyl compound (II) was cooled to 3±2 °C under nitrogen atmosphere. To this, 114.5 g of sodium tertiary butoxide was added drop wise followed by the addition of 112 g of 5-bromo-2-chloropyrimidine taken in 500 ml of 2-methyl THF. On completion of addition, the temperature of reaction mixture was raised to room temperature and reaction was stirred for 3-4 hours. Further, on completion of reaction (checked by TLC), was added 1000 ml of purified water. The pH of the solution was adjusted to 5-6 with 1N HCl. The layers were separated. Aqueous layer was extracted with 500 ml of 2-ethyl THF. Combined organic layer was washed sodium chloride solution. Organic layer was dried over sodium sulphate, further treated with charcoal and subjected to vacuum distillation at temperature 50±2 °C. The residue was stripped with 200 ml of ethyl acetate. Further, 300 ml of ethyl acetate was added and the mixture was heated to 60±2 °C to obtain clear solution. The clear solution was cooled to 27±2 °C, further chilled to 3±2 °C. Solid obtained was filtered and washed with 100 ml of ethyl acetate. The resulting solid was further treated with 400 ml of ethyl acetate and heated to 60±2 °C to obtain clear solution. The clear solution was cooled to 27±2 °C, further chilled to 3±2 °C. Solid obtained was filtered and washed with 100 ml of ethyl acetate. The solid was dried under vacuum at 43±2° C for 12 hours.
Dry weight: 80g
Purity % (HPLC): 99.92%

Example: 5
One pot synthesis of substantially pure Macitentan (I)
To 100 g of sulfamide compound (III) (prepared according to Example 1) was added 600 ml of ethylene glycol and 39.5 g of sodium hydroxide. The reaction mixture was heated at 96±3 °C and maintained for 6 hours. On completion of the reaction (checked by TLC), the reaction mixture was cooled to 27±2 °C. To the cooled mixture were added 800 ml of 2-methyl THF and 800 ml of purified water. The pH of the solution was adjusted to 1-2 with 1N HCl. The layers were separated. Aqueous layer was extracted with 500 ml of 2-methyl THF. Combined organic layer was washed with 800 ml of purified layer followed by washing of 2 x 500 ml 10% sodium chloride. The organic layer was dried over sodium sulphate and distilled under vacuum (up to 5 vol stage). The dried organic layer containing the hydroxy compound (II) was cooled to -5±5 °C under nitrogen atmosphere. To the cooled layer was added drop wise 132 g of sodium tertiary butoxide followed by addition of 120 g of 5-Bromo-2-chloro pyridine. The temperature of the reaction mixture was raised to 5±5 °C and reaction was stirred for 6 hrs. Further, on completion of reaction (checked by TLC), was added 1000 ml of purified water. The pH of the solution was adjusted to 5-6 with 1N HCl. The layers were separated. The organic layer was washed with purified water, sodium bicarbonate solution followed by sodium chloride solution. The organic layer was dried over sodium sulphate and subjected to distillation. The resulting residue was given stripping of 200 ml of methanol. Further, 500ml of methanol was added and the mixture was heated to 55±5 °C further cooled to 27±2 °C, further chilled to 13±3 °C. The solid obtained was filtered and washed with 100 ml of methanol. The resulting solid was further treated with 300 ml of ethyl acetate and heated to 63±3 °C to obtain a clear solution which was treated with charcoal. The clear solution was cooled to 27±2 °C and further chilled to 3±2 °C. Solid obtained was filtered and washed with 100 ml of ethyl acetate. The solid was dried under vacuum at 43±2 °C for 12 hours.
Dry weight: 80 g
Purity % (HPLC): 99.80%
,CLAIMS:1. A process for preparing macitentan of formula (I):

(I)
comprising:
reacting the compound of formula (II):

(II)

with 5-bromo-2-chloro pyrimidine in the presence of a suitable base and a polar aprotic solvent selected from the group comprising of 2-methyltetrahydrofuran, dialkylcarbonate and the like, to obtain a compound of formula (I); and optionally thereafter purifying the compound of formula (I) so formed.

2. A process according to claim 1, wherein the compound of formula (II) is prepared by reacting a sulfamide compound of formula (III):

with ethylene glycol in the presence of a suitable base.

3. A process according to claim 1 or claim 2, wherein the dialkylcarbonate is selected from dimethylcarbonate or diethylcarbonate.

4. A process according to claim 1 or claim 2, wherein the compound of formula (II) is not isolated from the reaction mixture as a solid.

5. A process according to claim 1 or claim 2, wherein the base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, or any combination thereof.

6. A process according to claim 5, wherein the base is sodium hydroxide.

7. A process according to any one of claims 2 to 6, wherein the molar ratio of ethylene glycol to compound of formula (III) is in the range from about 10:1 to about 1:1.

8. A process according to claim 7, wherein the molar ratio of ethylene glycol to compound of formula (III) is 6:1.

9. A process according to claim 2, wherein the process is carried out in the presence of a polar aprotic solvent.

10. A process according to claim 9, wherein the polar aprotic solvent is 2-methyltetrahydrofuran, a dialkylcarbonate or any combination thereof.

11. A process according to claim 10, wherein the solvent is 2-methyl tetrahydrofuran.

12. A process according to any one of claims 2 to 11, wherein the process is carried out at a temperature ranging from about room (ambient) temperature to about the reflux temperature of the solvent used.

13. A process according to any one of claims 2 to 12, wherein upon completion of the reaction the resulting reaction mixture is cooled and quenched using a suitable acid.

14. A process according to claim 13, wherein water is added to the reaction mixture following the addition of a suitable acid.

15. A process according to claim 13 or 14, wherein the reaction mass obtained upon completion of the process is extracted with an organic solvent selected from 2-methyltetrahydrofuran, a dialkylcarbonate or any combination thereof.

16. A process according to any one of claims 2 to 15, wherein the reaction mass obtained upon completion of the process is further treated with water to obtain an organic solvent layer and an aqueous layer, and optionally dried with a suitable drying agent.

17. A process according to claim 16, wherein the organic solvent layer is separated and cooled to a temperature between about 5 to about 0 ?C.

18. A process according to claim 17, wherein the temperature is 3±2 ?C.

19. A process according to claim 16, 17 or 18, wherein a suitable base is added to the organic solvent layer.

20. A process according to claim 19, wherein the base is an alkali metal hydroxide, optionally selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide, or any combination thereof.

21. A process according to any one of claims 16 to 20, wherein the temperature of the reaction mass is raised to about room (ambient) temperature and maintained at that temperature for 3 to 4 hours.

22. A process according to any preceding claim, wherein the compound of formula (II) is purified prior to reaction with 5-bromo-2-chloro pyrimidine using a solvent selected from the group consisting of C1-C4 alcohols, esters, ketones hydrocarbons, or any combination thereof.

23. A process according to any preceding claim, wherein the compound of formula (II) is purified prior to reaction with 5-bromo-2-chloro pyrimidine using a mixture of methanol and toluene.

24. A process according to any preceding claim, wherein the base is an alkali metal hydroxide, optionally selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide, or any combination thereof.

25. A process according to any preceding claim, wherein the compound of formula (I) is purified using a solvent selected from the group comprising C1-C4 alcohols, esters, ketones and any combination thereof.

26. A process according to claim 25, wherein the compound of formula (I) is purified using ethyl acetate.

27. A one-pot process for preparing macitentan of formula (I):

(I)

comprising the following steps:
a) reacting a compound of formula (III):

with ethylene glycol in the presence of a suitable base to obtain a compound of formula (II):

(II);
b) adding one or more suitable a polar aprotic solvents selected from the group comprising of 2-methyltetrahydrofuran, dialkylcarbonate and the like, and water, stepwise or simultaneously, to the resulting reaction mixture to form an organic layer and an aqueous layer;
c) separating the organic layer so formed;
d) adding a suitable base and 5-bromo-2-chloropyrimidine to the resulting organic layer to obtain a compound of formula (I);
e) isolating the compound of formula (I); and
f) optionally, purifying the compound so formed.

28. A process according to claim 27, wherein the base is an alkali metal hydroxide, optionally selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide, or any combination thereof.

29. A process according to claim 27 or 28, wherein the molar ratio of ethylene glycol to compound of formula (III) is in the range from about 10:1 to about 1:1.

30. A process according to any one of claims 27 to 29, wherein step b) is performed in a polar aprotic solvent selected from the group consisting of 2-methyltetrahydrofuran, a dialkylcarbonates, or any combination thereof.

31. A process according to claim 30, wherein the dialkylcarbonate is selected from dimethylcarbonate or diethylcarbonate.

32. A compound of formula (I):

having a chemical purity of greater than 99.5%.

33. A compound of formula (I) according to claim 32, prepared by a process according to any one of claims 1 to 31.

34. A process substantially as hereinbefore described with reference to any one of the Examples.