FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide (V1la).

BACKGROUND OF THE INVENTION
4-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2']-bipyrimidin-4-yi]benzene-sulfonamide monohydrate (I) is generically knovm as Bosentan monohydrate.

Bosentan is a specific competitive antagonist at endothelin receptor types ETA and ETB. Endothelin (ET-1) is a neurohormone, the effects of which are mediated by binding of ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role of ET-1. Bosentan has a slightly higher affinity for ETA receptors than ETB receptors.

Bosentan is marketed under the name Tracleer®. It has been approved for the treatment of pulmonary arterial hypertension (PAH).
Hoffmarm-La Roche disclosed Bosentan and its pharmaceutically acceptable salts in US 5,292,740. US 5,292,740 also discloses a process for the preparation of sodium salt of Bosentan (lb), by reacting 2-amidinopyrimidinium hydrochloride (II) with diethyl(2-methoxyphenoxy)malonate (III) in the presence of sodium metal in methanol followed by IN sodium hydroxide to produce 5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione (IV), which is further reacted with phosphorus pentachloride in presence of N,N-diisopropyl-N-ethylamine to produce 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V). Condensation of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V) with 4-(l,l-dimethylethyl)benzenesulfonamide (VI) in the presence of dimethylsulfoxide to produce 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII), which is then reacted with a sodium ethylene glycol in ethylene glycol solvent at 100°C to produce Bosentan as sodium salt (lb).


The major disadvantage with the above process is that the use of sodium ethylene glycol in a ethylene glycol solvent in the reaction of 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) to produce sodium salt of Bosentan (lb). Use of sodium ethylene glycol, which is a reagent difficult to prepare and leads to the formation of undesired ethylene glycol bis-sulfonamide (VIII), in which two molecules of the 4-(l,l-

dimethylethyl)-N- [6-chloro-5 -(2-methoxyphenoxy)- [2,2' -bipyrimidin] -4-yljbenzenesulfonamide (VII) are coupled with one molecule of ethylene glycol. The removal of this undesired ethylene glycol bis-sulfonamide (VIII) compound requires laborious purification steps to produce pharmaceutically suitable pure Bosentan.

US 6,136,971 discloses an alternative process for the preparation of Bosentan (la), by condensing 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) with mono protected sodium ethylene glycol in the presence of base in aprotic non-polar solvent to produce protected Bosentan (X). Treating protected Bosentan (X) with formic acid to produce formyl Bosentan (XI), which is further treated with base to produce Bosentan (la).

The above process involves multiple steps relating to the protection and de-protection and use of more expensive mono protected ethylene glycol. Hence, the above process is not suitable for commercial scale synthesis of Bosentan (la). WO 2009/004374 Al discloses a process for the preparation of Bosentan (la), by providing a mixture of ethylene glycol and hydroxide ions, followed by addition of 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) and isolating Bosentan (la).

When we carry out the reaction of 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) with ethylene glycol in the presence of sodium hydroxide to produce Bosentan (la), we have found the formation of about 0.34 % of bis-sulfonamide (VIII) impurity.
Hence, there is a need to develop a process, which does not involve multiple steps and involves inexpensive reagents, which allows Bosentan monohydrate (I) of high purity and improved yield.
The present invention provides a simple and cost effective process for the preparation of 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of Bosentan monohydrate with high purity and good yield on a commercial scale.
SUMMARY OF THE INVENTION
The present application provides a process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its sah,

(ii) condensing compound of Formula (II) with dimethyl-(2-methoxyphenoxy)malonate (III),


in presence of base other than sodium methoxide in a solvent to
produce 5-(2-methoxyphenoxy)-2-(pyrimidin-2-
yl)tetrahydropyrimidin-4,6-dione (IV),

(iii) treating the compound of Formula (IV) with halogenating agents to produce 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va),

in the presence of base in a solvent optionally in presence of phase transfer catalyst to produce compound of Formula (Vila) or its salts.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) or its salt.
The process comprises, treating 2-cyanopyrimidine (XII) with a base selected from alkoxides such as sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide and in a solvent selected from lower alkanol such as methanol, ethanol, isopropanol or butanol. The resulting reaction mixture is treated with ammonium chloride to produce 2-amidinopyrimidinium hydrochloride (II).
The reaction may be performed at a temperature ranging from about -10°C to about 10°C based on the solvents used for the reaction.

in the presence of a base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide to produce dimethyl-(2-methoxyphenoxy)malonate (III).

The reaction is carried out in a solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof. Preferred solvent is the toluene.
The reaction may be performed at a temperature ranging from about 20°C to about 150°C based on the solvents used for the reaction. The reagent dimethylchloro malonate (XIV) is added to the solution of salt of 2-methoxyphenol (XIII) in the organic solvent. More preferably, after removal of water from the solution by azeotropic distillation.
The sufficient period of time necessary for obtaining compound (III) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 1 to about 10 hours. More preferably, the reaction mixture is maintained for about 2 hour to about 3 hours.
Compound (III) can be isolated from the reaction mixture by adding a sufficient amount of water to the reaction mixture followed by aqueous base solution to remove unreacted 2-methoxyphenol (XIII) followed by removing the solvent to produce an oily mass.
Condensing the compound (III) with 2-amidinopyrimidinium hydrochloride (II) in the presence of a suitable base in a solvent to produce 5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione (IV).
The base is selected from alkoxide such as sodium ethoxide, sodium isoproxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide. The solvent used in the reaction is selected from lower alkanol such as methanol, ethanol, isopropanol or butanol.

The reaction may be performed at a temperature ranging from about -10°C to about 30°C based on the solvents used for the reaction. A preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 5 hours. Compound (IV) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, treating with a solvent and crystallizing or precipitating from the reaction medium. Preferably, a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 1 to pH of about 2, more preferably from pH of about 0.5 to pH of about 1.0. Any acid having sufficient pKa to generate the desired pH can be used. Preferably the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid. Preferably, the solvent used is selected from methylene chloride, ethyl acetate, and toluene.
5-(2-Methoxyphenoxy)-2-(pyrimidine-2-yl)-tetrahydropyrimidin-4,6-dione (IV) reacted with halogenating agent to produce 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va). The halogenating agent is selected from phosphorous oxychloride and phosphorous pentachloride. The reaction may be performed at a temperature ranging from about 20°C to about 120°C. A preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 8 hours. After completion of the reaction, the reaction mass was added to a mixture of organic solvent and water and treated with aqueous base. The organic layer was separated and treated with carbon. The resulting filtrate containing 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va) is used as such in the next step, without isolation or the compound (Va) is isolated from the reaction mixture by removing the solvent and crystallizing or precipitation from the solvents.
The solvent used is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform. The aqueous base used is selected from

alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxides, calcium hydroxide.
Reacting 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va) with 4-(l,l-
dimethylethyl)benzene sulfonamide (VI) in the presence of suitable base to
produce 4-( 1,1 -dimethylethy l)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-
bipyrimidin]-4-yl]benzenesulfonamide(VIIa).
The suitable base is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures thereof
The reaction is carried out in a solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof. Preferred solvent is the toluene.
The reaction may be performed in the presence of phase transfer catalyst, which is
selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide,
tetrabutylammonium chloride, tetrabutylphosphonium chloride,
benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate. Preferably, tetrabutylammonium bromide.
The reaction is performed at a temperature ranging from about 30°C to about 150°C based on the solvents used for the reaction. More preferably, from about 25°C to about 120°C. A preferred reaction time is from about 1 to about 7 hours, more preferably from about 1 to about 5 hours.

Water formed during the reaction is separated by azeotropically. 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, extracting with a solvent and removing the solvent and crystallizing or precipitating it from a crystallization solvent. Preferably, a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 0.5 to pH of about 4, more preferably, from pH of about 0.5 to pH of about 1. Any acid having sufficient pKa to generate the desired pH can be used. Preferably the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid. Preferably, the solvent used in the extraction is selected from methylene chloride, ethyl acetate, and toluene.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES:
Example-1
Stage-1:
Preparation of dimethyI-(2-methoxyphenoxy)malonate (III)
2-Methoxyphenol (XIII) (lOOg, 805.54 mmol) was dissolved to toluene (700 ml) at 20-30°C and sodium hydroxide (33.83g, 845.75 mmol) was added. The reaction mass was heated to reflux temperature and separated water azeotropically. Thereafter, dimethyl chloromalonate (147.6g, 886.16 mmol) was added at 60-65''C over a period of 30 min and heated to reflux temperature and stirred for 3 hrs. The reaction mass was cooled to room temperature, washed with DM water followed by 1% w/v aqueous sodium hydroxide solution and concentrated to yield 195g of the title compound.

Stage-2:
Preparation of 2-amidinopyrimidinium hydrochloride (II)
2-Cyanopyrimidine (XII) (50g, 475.73 mmol) was added to the solution of sodium ethoxide (3.24g, 47.64 mmol) in methanol (500 ml) at -3 to 0°C and was stirred for 8 hrs. The reaction mass was allowed to a temperature of 25-30°C and treated with ammonium chloride (26.72g, 499.43 mmol) to yield 2-amidinopyrimidinium hydrochloride (II).
Stage-3:
Preparation of 5-(2-niethoxyphenoxy)-2-(pyriniidin-2-yl)-
tetrahydropyriniidin-4,6-dione (IV).
Dimethyl(2-methoxyphenoxy)malonate (III) was added to the reaction mass containing 2-aminopyrimidinium hydrochloride (II) prepared in stage-2 at 0-5°C. Sodium ethoxide (106.76g, 1570 mmol) was added to the reaction mass at 0-5°C in 1 hrs and maintain at 35°C for 5hrs. Thereafter, the reaction mass was concentrated, dissolved in mixture of DM water (500ml) and toluene (150ml) and acidified to pH 0.5-0.7 with dilute hydrochloric acid at 20-30''C. The precipitated product was fihered, washed with toluene followed by water and dried at 75-80°C to yield 129.3g of title compound. Chromatographic purity: 96.61% (by HPLC, by area normalization)
Stage-4:
Preparation of 4-(l,l-dimethylethyl)-N-[6-chIoro-5-(2-methoxyphenoxy)[2,2'-
bipyrimidin]-4-yl]benzenesulfonamide(VII).
5-(2-Methoxyphenoxy)-2-(pyrimidin-2-yl)-tetrahydropyrimidin-4,6-dione (IV) (lOOg, 320.22mmol) was added to phosphorous oxychloride (196.4g). The resulting reaction mass was slowly heated to 103-105''C and stirred for 4 hrs. The reaction mass was added to a mixture of toluene (450ml) and water (350ml) at 20-50°C and treated with 30% w/w aqueous sodium hydroxide solution (271.5ml) at 70-80°C. The organic layer was separated and treated with activated carbon (7g) at 80-90''C for 30min, filtered through hyflo and washed with hot toluene (300ml).

4-( 1,1-Dimethylethyl)benzene sulfonamide (VI) (68.3g, 320.2mmol) was added to the filtrate, followed by potassium carbonate (53.03g, 384.27 mmol) and tetrabutylammonium bromide (3.19g, 9.59 mmol) were added, heated to reflux temperature and separated water azeotropically for 2 hrs, the reaction mass was cooled to 20-25''C, filtered the solid and dried. Further, the solid was added to DM water and acidified to pH 0.5 to 0.7 with hydrochloric acid. The solid was filtered washed with DM water and dried to yield 144.5g of title product. Chromatographic purity: 97.92% (by HPLC, by area normalization)

1. A process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (V11a) or its salt,

(ii) condensing compound of Formula (II) with dimethyl-(2-methoxyphenoxy)malonate (III),
O OCH3
MeO^'^Y^y^ Formula III
MeO^O ^

in the presence of base other than sodium methoxide in a solvent to
produce 5-(2-methoxyphenoxy)-2-(pyrimidin-2-
yl)tetrahydropyrimidin-4,6-dione (IV),
in the presence of base in a solvent optionally in presence of phase transfer catalyst to produce compound of Formula (V1la) or its sahs.
2. The process according to claim 1, wherein base used in step (i) or step (ii) is selected from alkoxide.
3. The process according to claim 2, wherein alkoxide is selected from sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isoproxide, potassium tert-butoxide.

4. The process according to claim 1, wherein solvent used in step (i) or step (ii)
is selected from lower alkanol such as methanol, ethanol, isopropanol or
buatnol.
5. The process according to claim 1, wherein halogenating agents in step (iii) is
selected from phosphorous oxychloride or phosphorous pentachloride.
6. The process according to claim 1, wherein base used in step (iv) is selected
from alkali or alkaline earth metal carbonate.
7. The process according to claim 1, wherein solvent used in step (iv) is
selected from aromatic hydrocarbons, halogenated hydrocarbon, polar
aprotic solvents or mixtures thereof.
8. The process according to claim 1, wherein phase transfer catalyst used in
step (iv) is selected from tetrabutylammonium bromide,
tetrabutylphosphonium bromide, tetrabutylammonium chloride,
tetrabutylphosphonium chloride, benzyltriethylammonium chloride,
tetrabutylammonium hydrogen sulfate.
9. The process as claimed in claim 1, wherein 4-(l,l-dimethylethyl)-N-[6-
halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide
(V11a) or its salt is converted to Bosentan monohydrate (I).