WO2013186706A1

WO2013186706A1 - Process for the preparation of bosentan

Info

Publication number: WO2013186706A1
Application number: PCT/IB2013/054784
Authority: WO
Inventors: Rajiv Indravadan Modi; Omprakash Gudaparthi; Anil Shankar Chowdhary; Neeraj Kumar; Sharad Natthu GAVALE; Sanjay Kanhaiyalal SONI; Nilesh Govind PATEL; Unnat Priyavadan PANDIT
Original assignee: Cadila Pharmaceuticals Ltd
Current assignee: Cadila Pharmaceuticals Ltd
Priority date: 2012-06-12
Filing date: 2013-06-11
Publication date: 2013-12-19
Anticipated expiration: 2014-12-12
Also published as: JP2015521594A

Description

Process for the preparation of Bosentan

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Bosentan monohydrate substantially free of impurities like ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide. BACKGROUND OF THE INVENTION

Bosentan, represented by formula I and chemically named as 4-t-butyl-N-(6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2, 2'-bipyrimidin-4-yl) benzenesulfonamide is a dual endothelin receptor antagonist (ERA). It is used for the treatment of pulmonary arterial hypertension (PAH).

Formula I

US 5292740 (Herein referred as US '740) discloses a process for the preparation of Bosentan and method of use as an inhibitor of endothelin receptor. The process of US '740 involves the condensation of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine with 4-tert- butyl benzenesulfonamide in DMSO to provide N-[6-chloro-5-(2-methoxy phenoxy)-2,2'- bipyrimidin-4-yl]-4-(l,l-dimethylethyl)benzenesulfonamide, subsequently react with sodium ethylene glycolate to yield Bosentan sodium. Product obtained by this process requires purification using column chromatography bring critical impurities like ethylene glycol bis- sulfonamide dimer (Formula r ) and 6-hydroxy sulfonamide (Formula V) under conrol.

US 6136971 disclose a process for the preparation of Bosentan. The process involves condensation of 4,6-dichloro-5-(o-methoxy phenoxy)-2,2'-bipyrimidine with 4-tert- butylbenzenesulfonamide to yield N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]-4- (1,1-dimthylethyl) benzene sulfonamide which is further reacted with protected ethylene glycol (mono t-butyl ethylene glycol ether) to yield protected bosentan, wherein ethylene glycol bis- sulfonamide dimer impurity was controlled. The protected group is removed using formic acid yielding Bosentan formate, which was hydrolyzed with sodium hydroxide to obtain Bosentan. WO2009004374 discloses the use of hydroxyl ion as a base with ethylene glycol, during the conversion of N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l- dimthylethyl) benzene sulfonamide to Bosentan. Use of hydroxyl ion controls the formation of ethylene glycol bis-sulfonamide dimer but removal of 6-hydroxy sulfonamide impurity (0.3% as exemplified) is not satisfactory achieved as per the description demonstrated in given examples.

WO2012020421 discloses a process for preparation of Bosentan to control ethylene glycol bis-sulfonamide dimer (formula IV) and 6-hydroxy sulfonamide (formula V) impurity by preparation of ammonium salt. However, Org. Process Res. Dev., 2011, 15 (6), pp 1382-1387 (OPRD) discloses similar process wherein 6-hydroxy impurity is not removed completely by purification of Bosentan ammonium. Bosentan base is purified to remove the impurity.

Therefore there is an industrial challenge to provide a process for preparing Bosentan maintain the impurity levels as per ICH guidelines. Ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide analogue as impurity are controlled or removed during the preparation of Bosentan. The present invention discloses a process for the preparation of pure Bosentan monohydrate resulting substantially free of ethylene glycol bis-sulfonamide dimer (formula IV) and 6-hydroxy sulfonamide (formula V) impurity. SUMMARY OF THE INVENTION

The main object of present invention is to provide a process for the preparation of Bosentan or pharmaceutical acceptable salts or hydrates thereof, with improved yield and quality of the product.

Another object of present invention is to provide the process for the preparation of Bosentan monohydrate by formation of amorphous Bosentan sodium.

Yet another object of present invention is to provide the process for the preparation of Bosentan monohydrate by formation of Bosentan ammonium.

Yet another object of present invention is to provide the process for the preparation of Bosentan sodium and Bosentan ammonium.

Yet another object of the present invention is to provide the process for the conversion of Bosentan sodium to Bosentan ammonium.

Yet another object of present invention is to provide a process for the preparation of Bosentan monohydrate having purity greater than 99.7%. BRIEF DESCRIPTION OF THE FIGURES

Figure 1: X-ray diffraction spectrum of crystalline Bosentan sodium. Figure 2a & 2b: HPLC of crude Bosentan sodium and pure Bosentan sodium.

Figure 3: HPLC of amorphous Bosentan ammonium salt.

Figure 4: X-ray diffraction spectrum of amorphous Bosentan sodium.

Figure 5: X-ray diffraction spectrum of amorphous Bosentan ammonium

Figure 6: X-ray diffraction spectrum of Bosentan monohydrate.

Figure 7a & 7b: DSC & TGA of Bosentan monohydrate.

Figure 8: HPLC of Bosentan monohydrate prepared from Bosentan sodium.

Figure 9: HPLC of Bosentan monohydrate prepared from Bosentan ammonium.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of Bosentan substantially free of ethylene glycol bis-sulfonamide dimer (formula IV) and 6-hydroxy sulfonamide (formula V) impurity. The present invention provides a process for preparing Bosentan with improved yield and quality as compared to prior art processes.

Formula-IV Formula V

Ethylene glycol bis-sulfonamide dimer 6-hydroxy sulfonamide analogue of Bosentan

The process according to present invention involves the preparation of Bosentan comprises following steps:

a) condensing N- [6-chloro-5- (2-methoxyphenoxy) [2,2'-bipyrimidin] -4-yl] -4- ( 1 , 1 -dimethyl ethyl) benzenesulfonamide (formula VI) with sodium ethylene glycolate;

b) purifying and isolating Bosentan sodium (formula II);

c) converting Bosentan sodium (formula II) to Bosentan ammonium; and

d) converting Bosentan ammonium in to bosentan monohydrate.

According to present invention the condensation of N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] -4- (1,1 -dimethyl ethyl )benzene sulfonamide with sodium ethylene glycolate is carried out in presence of metal or a base. The metal is selected form Na, Li, K, Mg. Preferred metal is sodium. The base is selected from inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide.

The reaction is carried out with or without using solvent. The ratio of sodium source and ethylene glycol used for the preparation of sodium ethylene glycolate is controlled to improve quality and yield of crude Bosentan sodium (formula II). Thus improves the process and also reduces the level of impurities. According to present invention the ration of sodium metal to ethylene glycol is ranging from 4-8:15-20 by w/v, preferably the ratio is 6:15 by w/v.

Formula II

Bosentan sodium is further purified using organic solvent or mixture of organic solvents with or without water to obtain crystalline Bosentan sodium having reduced level of ethylene glycol bis- sulfonamide dimer (formula IV) and 6-hydroxy sulfonamide (formula V) impurities.

The solvent is selected from C₂-C6 alkyl acetates such as ethyl acetate, isopropyl acetate, butyl acetate; C₁-C5 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ter- butanol, n-pentanol; aliphatic chlorinated hydrocarbons such as Dichloromethane, Dichloroethane; ethylneglycol, water and mixtures there of wherein preferred solvents are Ethyl acetate : Methanol and Dichloromethane: water

Conversion of crystalline Bosentan sodium to Bosentan ammonium comprises following steps: a) dissolving Bosentan sodium in a solvent;

b) pH of the solution is adjusted using acid; c) reaction mixture was concentrated and pH adjusted to 9-10 using ammonia; d) isolating Bosentan ammonium.

wherein solvent used in step-a is selected from aliphatic chlorinated hydrocarbons such as Dichloromethane, dichloroethane, water and mixtures thereof. Preferable mixture of solvents is dichloromethane and water.

wherein acid used in step-b is selected from inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p - toluene sulphonic acid, methane sulphonic acid or benzene sulphonic acid; and organic acid such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid.

Thus obtained Bosentan ammonium is converted to Bosentan monohydrate and the process comprises following steps:

a) dissolving Bosentan ammonium in a solvent;

b) pH of the reaction is adjusted using an acid;

c) isolating Bosentan Monohydrate.

wherein solvent used in step-a is selected from is selected from C3-C₆ Ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone ; aromatic hydrocarbons such as toluene, xylene; C₁-C5 alkyl alcohol such as methanol, ethanol, propanol, iso-propanol, n-butanol, tert- butanol, n-pentanol; C₂-C₆ alkyl acetates such as ethyl acetate, isopropyl acetate, butyl acetate; C₂-Cg ethers such as diethyl ether, isopropyl ether, methyl tertiary butyl ether; water, Denatured spirit and combination thereof. Preferred solvent used in step-a is denatured spirit.

wherein acid used in step-b is selected from inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p - toluene sulphonic acid, methane sulphonic acid or benzene sulphonic acid; organic acid such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid.

The process for the preparation of Bosentan comprises the steps of:

A) condensing N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l-dimethyl ethyl) benzene sulfonamide with sodium ethylene glycolate in the presence of a metal or a base;

b) isolating amorphous Bosentan sodium in organic solvent;

c) converting amorphous Bosentan sodium to Bosentan ammonium;

d) converting Bosentan ammonium to Bosentan monohydrate. The condensation of N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l- dimethyl ethyl)benzene sulfonamide with sodium ethylene glycolate is carried out in presence of metal or a base.

wherein metal is selected form Na, Li, K and Mg, preferably metal is sodium or the base is selected form inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide. The reaction is carried out with or without using solvent. The ratio of sodium source and ethylene glycol used for the preparation of sodium ethylene glycolate is controlled to improve quality and yield of crude Bosentan sodium (formula II) having reduced level of impurities. According to present invention the ratio of sodium metal to ethylene glycol is ranging from 4- 8:15-20 by w/v, preferably the ratio is 6:15 by w/v. After completion of the reaction, reaction mixture is extracted with organic solvent, with out further quenching with water.

The organic solvent used for the extraction includes but not limited to aliphatic chlorinated hydrocarbons such as dichloromethane, dichloroethane; more particularly, the solvent used is Dichloromethane .

Ethylene glycol layer and DCM layer are separated. Thus obtained ethylene glycol can be recycled and used in further reactions. DCM layer thus obtained is concentrated.

wherein organic solvent used in step-b is selected form higher n-alkane such as hexane, heptane, octane and the like; C₂-C8 ethers such as diethyl ether, isopropyl ether, methyl tertiary butyl ether or combination thereof. Preferred solvents are isopropyl ether or hexane.

Bosentan sodium is converted to Bosentan ammonium comprising following steps;

a) dissolving Bosentan sodium in a solvent;

b) pH of the solution is adjusted using acid;

c) reaction mixture was concentrated and pH adjusted to 9-10 using ammonia;

d) isolating Bosentan ammonium.

wherein solvent used in step-a is selected from aliphatic chlorinated hydrocarbons such as Dichloromethane, dichloroethane; water and mixtures thereof preferable solvent mixture is dichloromethane and water.

wherein acid used in step-b is selected from inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p - toluene sulphonic acid, methane sulphonic acid or benzene sulphonic acid; and organic acid such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid. Reaction mixture was concentrated and pH adjusted to 9-10 using ammonia to obtain Bosentan ammonium. Thus obtained Bosentan ammonium is converted to Bosentan monohydrate comprising following steps:

a) dissolving Bosentan ammonium in a solvent;

b) pH of the reaction is adjusted using an acid;

c) isolating Bosentan Monohydrate. wherein solvent used in step-a is selected from is selected from C3-C6 Ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; C1-C5 alkyl alcohol such as methanol, ethanol, propanol, iso-propanol, n-butanol, tert-butanol, n-pentanol; C₂-C8 ethers such as diethyl ether, isopropyl ether, methyl tertiary butyl ether; water, Denatured spirit and combination thereof wherein preferred solvent is selected from Denatured spirit

The formation of amorphous Bosentan ammonium reduces the impurity levels of ethylene glycol bis- sulfonamide dimer and 6-hydroxy sulfonamide.

In another embodiment, the present invention provides Bosentan ammonium comprising less than 0.1%, preferably less than 0.05%, and more preferably less than 0.02% of 6-hydroxy sulfonamide impurity and comprising less than 0.1%, preferably less than 0.05%, and more preferably less than 0.02% ethylene glycol bis-sulfonamide dimer impurity.

As used herein, "pure Bosentan monohydrate" which is substantially free of dimer and pyrimidone impurities. Namely it refers to Bosentan monohydrate wherein the total impurities is less than about 0.3% w/w as measured by high performance liquid chromatography ("HPLC"), and each individual impurity is less than about 0.15% w/w as measured by HPLC, Preferably, the total impurities is less than about 0.2% w/w as measured by HPLC, and each individual impurity is less than about 0.1% w/w as measured by HPLC; still more specifically the total impurities is less than about 0.1% w/w as measured by HPLC, each individual impurity is less than about 0.02% w/w as measured by HPLC; . X-ray diffraction spectrum reported herein were recorded with PAN analytical Xpert PRO MPD DY-3240 X-ray diffractometer model using CuK alpha radiation having the wavelength 1.541°A, Goniometer PW3050, tube current 40mA, tube tension 45kV, scanning speed 2 min, scanning type continuous.

DSC and TGA patterns were recorded using TA instruments-Q20 and TA instruments- Q50, respectively using the standard analytical techniques.

The above described process is cost-effective and reproducible on industrial scale wherein the levels of impurities are controlled at intermediate stage to give Bosentan in high yield and purity. The present invention is further illustrated by following non-limiting examples. Example 1: Preparation of N-r6-chloro-5-(2-methoxyphenoxy)r2,2'-bipyrimidin1-4-yl1-4- (1,1-dimthylethyl) benzene sulfonamide sodium:

150 gm of 5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl) tetrahydro-pyrimidine-4,6-dione is added to a stirred solution of 246 gm of POCl₃ in 150 ml toluene. The reaction mixture is stirred for 30 minutes. The temperature of reaction mixture is gradually raised and maintained. The reaction mixture is concentrated and stripped off using toluene. The reaction mixture is then cooled. Toluene is charged to the reaction mixture. The reaction mixture is quenched with water. After stirring, the layers separated. The organic phase was washed with sodium bicarbonate solution and concentrated under vacuum to obtain crude mass. Then, 4-t-butylbenzene sulphonamide (91.73 gm), Na₂C0₃ (90.95 gm) and DMF (750 ml) were added to the crude mass and resulting mixture was stirred for 15-30 minutes.

The reaction mixture was heated at 110-115°C and then concentrated under reduced pressure. The residue was quenched with water and stirred. Solid mass was isolated and purified using isopropanol to give titled compound. Chromatographic purity is obtained >98%. Example 2: Preparation of Bosentan sodium (crystalline form):

26.16 gm of Sodium was slowly added to 1500 ml of ethylene glycol at below 40°C under nitrogen and the resulting mixture was stirred to obtain clear solution. The solution of N-[6- chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l-dimethyl ethyl) benzene- sulfonamide (100 g) in ethylene glycol was charged to the reaction mixture. The contents were heated and maintained. The reaction mixture was monitored by HPLC wherein 0.24% of ethylene glycol bis-sulfonamide dimer, 1.02% of 6-hydroxy sulfonamide, starting material (monochloro impurity) 0.14% was observed. The reaction mixture was then cooled to 30-35°C and quenched with water followed by addition of dichlorome thane and stirred for 15 minutes. The organic phase was separated and further stirred; the precipitated crystals were filtered, washed with dichloromethane and dried to give crystalline Bosentan sodium (103.5g).

HPLC Analysis:

HPLC Purity: 99.27%, Ethylene glycol bis-sulfonamide dimer impurity: 0.04%, 6-hydroxy sulfonamide impurity: 0.15%, Starting material (monochloro impurity)-0.05% Example 3: Preparation of Bosentan sodium (crystalline form):

A mixture of N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l-dimethyl ethyl) benzene sulfonamide (150 g), sodium hydroxide (64.80 gm) and ethylene glycol (2250 ml) was stirred at 78-82°C. The reaction mixture contains 0.3% of ethylene glycol bis-sulfonamide dimer, 1.3% of 6-hydroxy sulfonamide, starting material (monochloro impurity) 0.08%, was then cooled. The reaction mixture was quenched with water followed by addition of dichloromethane and stirred.

The organic phase was separated further stirred; crystals were filtered, washed with dichloromethane and dried to give crystalline Bosentan sodium (103.6 g).

HPLC Analysis:

HPLC Purity: 99.38%, Ethylene glycol bis-sulfonamide dimer impurity: 0.03%, 6-hydroxy sulfonamide impurity: 0.32%, starting material (monochloro impurity) -Not detected. Example 4: Preparation of Bosentan sodium (amorphous form):

Sodium (26.16 gm) was slowly added to ethylene glycol (1500 ml) below 40°C under nitrogen and the resulting mixture was stirred to obtain clear solution. The solution of N-[6- chloro-5-(2-methoxyphenoxy)[2,2'-bipyrirnidin]-4-yl]-4-(l,l-dimethylethyl)benzene

sulfonamide (100 g) in ethylene glycol (500 ml) was charged to the reaction mixture. The contents were heated to about 80°C and maintained. The reaction mixture containing 0.34% of ethylene glycol bis-sulfonamide dimer, 1.26% of 6-hydroxy sulfonamide was then cooled to . Dichloromethane is added to the reaction mixture and stirred for 15 minutes. Ethylene glycol layer and DCM layer are separated. Ethylene glycol layer obtained can be recovered and reused in further reactions. DCM layer was distilled under vacuum to obtain solid. Di isopropyl ether was charged to the solid at low temperature and contents were stirred, filtered, washed with Di isopropyl ether and dried to yield amorphous Bosentan sodium (102.0 g).

Chromatographic purity is >99%. Example 5: Purification of Bosentan sodium:

Ethyl acetate (700 ml) and methanol (300 ml) were charged to crude Bosentan sodium (100 gm). The contents were stirred at about 68°C. Suspension was then cooled and further stirred. Solid was isolated by filtration, washed with mixture of ethyl acetate and methanol, and dried to obtain pure crystalline Bosentan sodium (75.0 g).

HPLC Analysis:

HPLC Purity: 99.79%, 6-hydroxy sulfonamide impurity: 0.05%, Ethylene glycol bis- sulfonamide dimer -Not detected, Starting material (monochloro impurity) -Not detected

Crystalline form of Bosentan sodium is characterized by its XRPD pattern having characteristic peaks at 6.62, 7.05, 7.85, 8.04, 8.75, 9.04, 9.42, 10.21, 12.78, 15.62, 15.78, 16.10, 16.67, 17.1, 18.58, 22.52, 23.95 and 25.19 + 0.2 degrees 2 theta and XRPD pattern is as per Figure- 1. Example 6: Purification of Bosentan sodium:

Ethylene glycol was charged to crude Bosentan sodium (100 gm) and heated at 70-80°C to get clear solution. Dichloromethane and water were added to the solution at 25-30°C and stirred for 15 minutes. The organic phase was separated, further stirred, crystals were filtered, washed with dichloromethane (100 ml) and dried to give crystalline Bosentan sodium (95.0 g) in purity >99.5% by HPLC analysis.

Crystalline form of Bosentan sodium is characterized by its XRPD pattern having characteristic peaks at 6.62, 7.05, 7.85, 8.04, 8.75, 9.04, 9.42, 10.21, 12.78, 15.62, 15.78, 16.10, 16.67, 17.1, 18.58, 22.52, 23.95 and 25.19 + 0.2 degrees 2 theta and XRPD pattern is as per Figure-1 Example 7: Preparation of Bosentan ammonium (amorphous):

Bosentan sodium (25 gm), dichloromethane (125 ml) and water (125 ml) were stirred for 15 minutes at 25-30°C. pH of solution was adjusted between 2-3 using acid and stirred for 30 minutes. The reaction mixture was concentrated and dichloromethane (125 ml) was added to concentrated mass. pH of reaction mixture was adjusted to using aqueous ammonia solution and stirred for 6 hours at 25-30°C. Solid was isolated by filtration, washed with dichloromethane and dried to obtain amorphous Bosentan ammonium (18.0 g).

HPLC Analysis:

HPLC Purity: 99.91%, 6-hydroxy sulfonamide impurity: 0.02%, Ethylene glycol bis- sulfonamide dimer-Not detected, Starting material (monochloro impurity)-Not detected Example 8: Preparation of Bosentan monohydrate:

Bosentan ammonium (130 gm) was added to SDS (650 ml) in a four-necked and heated for 30 minutes. Thereafter, the reaction mixture was cooled and pH of the solution was adjusted to 3 with aq. hydrochloric acid. The reaction mixture was filtered and the reminder was washed with a mixture of SDS and water. Filtrates were combined and water (455 ml) was added and stirred for 4-5 hours with cooling at 25°C. The product was isolated by filtering and further washed with water. The solid was dried to give Bosentan monohydrate (116.0 g).

HPLC Analysis:

HPLC Purity: 99.87%, 6-hydroxy sulfonamide impurity: 0.02%, Ethylene glycol bis- sulfonamide dimer impurity-Not detected, Starting material (monochloro impurity) -Not detected Example 9: Preparation of Bosentan monohydrate:

Bosentan sodium (68 gm) was added to SDS (650 ml) in a four-necked and heated for 30 minutes. Thereafter, the reaction mixture was cooled and pH of the solution was adjusted to 3 with aq. hydrochloric acid. The reaction mixture was filtered and the reminder was washed with a mixture of SDS and water. Filtrates were combined and water was added and stirred for 4-5 hours with cooling at 25°C. The product was isolated by filtering and further washed with water. The solid was dried to give Bosentan monohydrate (116.0 g). HPLC Analysis:

HPLC Purity: 99.81%, 6-hydroxy sulfonamide impurity: 0.04%, Ethylene glycol bis- sulfonamide dimer impurity-Not detected, Starting material (monochloro impurity)-Not detected

The product obtained by following above given non-limiting examples is resulting Bosentan monohydrate substantially free of impurities like ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide. The process according to present invention is producing Bosentan or pharmaceutical acceptable salts and hydrates thereof, with improved yield and quality of the product.

Claims

We claim,

1. A process for the preparation of bosentan monohydrate comprising the steps of:

(a) condensing N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l- dimethylethyl) benzenesulfonamide with sodium ethylene glycolate in the presence of metal or a base to give bosentan sodium;

(b) purifying and isolating bosentan sodium;

(c) converting bosentan sodium to bosentan ammonium;

(d) converting bosentan ammonium to bosentan monohydrate.

2. A process for the preparation of Bosentan sodium, comprising following steps:

(a) condensing N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-4-(l,l- dimethylethyl) benzenesulfonamide with sodium ethylene glycolate in the presence of metal or a base;

(b) extraction of reaction mixture with organic solvent;

(c) isolating bosentan sodium using organic solvent.

3. The process as claimed in claim- 1 or 2, wherein the base used in step (a) is inorganic base.

4. The process as claimed in claim-1 or 2, wherein the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide.

5. The process as clamed in claim-1, wherein purification of Bosentan sodium is carried out comprising the steps of:

(a) dissolving crude Bosentan sodium in organic solvent selected from C₂-C6 alkyl acetates such as ethyl acetate, isopropyl acetate, butyl acetate; C₁-C5 alkyl alcohol such as methanol, ethanol, propanol, iso-propanol, n-butanol, tert-butanol, n- pentanol; aliphatic chlorinated hydrocarbons such as Dichloromethane, Dichloroethane; water or mixtures thereof;

(b) heating the reaction mixture up to 80°C;

(c) isolating pure crystalline bosentan sodium.

6. The process as claimed in claim-5, wherein the solvent used in step-a is selected from a mixture of solvents from Ethyl acetate: Methanol or Dichloromethane: Water.

7. The process as claimed in claim-1, wherein conversion of Bosentan sodium to Bosentan ammonium comprising the steps of:

(a) dissolving Bosentan sodium in organic solvent;

(b) pH of the reaction mixture is adjusted using acid; (c) reaction mixture was concentrated and pH adjusted using ammonia;

(d) isolating Bosentan ammonium in an amorphous form.

8. A process as claimed in claim-7, wherein solvent used in step-a is selected from aliphatic chlorinated hydrocarbons, water or mixtures thereof.

9. The process as claimed in claim- 1, wherein bosentan ammonium is converted to Bosentan monohydrate comprising the steps of:

(a) dissolving Bosentan ammonium in a solvent selected from C3-C₆ Ketones; aromatic hydrocarbons; C1-C5 alkyl alcohol; C₂-C₆ alkyl acetates; water, Denatured spirit or mixtures thereof;

(b) pH of the reaction mixture is adjusted using an acid;

(c) isolating Bosentan Monohydrate.

10. The process as claimed in claim-2, wherein the organic solvent used in step-b is selected from aliphatic chlorinated hydrocarbons such as Dichloromethane and Dichloroethane.

11. The process as claimed in claim-2, wherein the solvent used in step-c is selected from aliphatic hydrocarbons such as hexane, heptane and the like;C₂ -C₆ ethers such as diethyl ether, isopropyl ether, methyl tertiary butyl ether and the like or combination thereof.

12. The process as claimed in claim 2, wherein bosentan sodium is obtained in an amorphous form.

13. Amorphous bosentan sodium.

14. Bosentan monohydrate having purity greater than 99.7% substantially free of ethylene glycol bis- sulfonamide dimer of formula IV.

Formula-IV

15. Bosentan monohydrate having purity greater than 99.7% substantially free of 6-hydroxy sulfonamide of formula V.

14