IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN
Field of Invention:
The present invention is directed to the improved process for preparing bosentan. Bosentan is chemically known as 4-(l,l-Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide monohydrate, having structural formula-1.

Background of the Invention:
Bosentan is found to be a potential inhibitor of endothelin receptors. Endothelin has recently been shown to play a pivotal role in the development of pulmonary hypertension and elevated endothelin concentrations have been found to be strongly correlated with disease severity. Endothelin antagonists especially bosentan, are therefore considered to represent a new approach to the treatment of pulmonary hypertension. The selective nonpeptide mixed endothelin ETA and ETR receptor antagonist bosentan (Tracleer®) has become the first endothelin antagonist to reach the market for pulmonary hypertension. It has a greater significance because until now only few drugs have been specifically approved for the indication of pulmonary hypertension. Bosentan can also be used for treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris.
Bosentan and its analogues as potential endothelin inhibitors have been first disclosed in US patent No. 5,292,740. The patent also disclosed the methods for preparing these compounds. One of the methods involves the condensation of diethyl (2-methoxyphenoxy) malonate with pyrimidine-2-carboxyamidine in presence of sodium ethoxide, followed by treatment with sodium hydroxide to provide the dihydroxy derivative, which is converted into dichloro derivative by treatment with refluxing

phosphorus oxychloride. One chlorine of the dichloro derivative is replaced by 4-tert-butylbenzenesulfonamide. The remaining chlorine is replaced by ethylene glycol in presence of sodium metal to provide bosentan.
The method of preparing ethylene glycol sulfonamide derivatives involves reacting an appropriately substituted pyrimidine monohalide with a monoanion ethylene glycol (e.g., sodium ethylene glycol) typically using ethylene glycol as a solvent. The mono sodium ethylene glycol is prepared by treating ethylene glycol with sodium metal which is difficult to handle at large scale in an industrial process. However, one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol. The removal of this bis sulfonamide requires costly and laborious separation steps to obtain a pharmaceutically suitable ethylene glycol sulfonamide compound. In addition, the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation. Another drawback is the need for isolating a pyrimidine dihalide which is believed to be a potent sensitizer. This problem is further complicated by the use of a halogenated solvent e.g., methylene chloride, during the isolation of pyrimidine dihalide, Halogenated solvent is expensive to dispose off properly, thus leading to added cost. In the final stages isopropyl ether is used for purification by recrystallisation which is not advisable as per ICH guidelines. Further more the synthesis requires at least six separate isolation steps and the use of many different solvents, which makes it economically less viable as an industrial process.
US Patent No 6,136,971 discloses a process which tries to overcome the disadvantages observed in the above process. It discloses a process for the preparation of 1,2-diheteroethylene sulfonamide i.e. bosentan, which involves the reaction of appropriately substituted pyrimidine monohalide intermediate with a mono protected 1,2-diheteroethylene anion to produce the monoprotected 1,2-diheteroethylene sulfonamide. The process involves additional steps of preparation of mono protected ethylene glycol, and removal of protecting group of mono-protected ethylene glycol sulfonamide. Hence

the process is more time consuming, laborious, involves use of more reagents and solvents, decreased yields, which increases the overall cost of the product.
Therefore there is a need for a process for preparing the 1,2-diheteroethylene sulfonamide i.e., bosentan with a reduced number of reaction product isolation steps. There is a need for a process for preparing bosentan which does not produce undesired 1,2-diheteroethylene bis-sulfonamides. Also there is a need for a process for preparing bosentan which does not require isolation of potent sensitizers such as pyrimidine dihalide intermediates.
There is a need to develop a process which can provide better yields and purity and which can be performed at an industrial scale. Till date there is no reference of bosentan morphology. Morphology plays an important role during the formulation of an active pharmaceutical ingredient.
The present invention overcomes the disadvantages of the processes of prior art. It is easier to perform as it involves lesser number of steps, utilizes milder reagents and reaction conditions, which are conducive to be scaled up to an industrial level. It is cost effective and economically viable process. The present invention also provides bosentan of a morphology which is highly advantageous for formulations.
Brief Description of the Invention:
The present invention relates to an improved process for the synthesis of bosentan. The process involves the preparation of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7) and its condensation with ethylene glycol in presence of a base and a suitable solvent with or without a phase transfer catalyst to provide bosentan (1).
Advantages of the Present Invention:
• The major advantage of the process is that it involves the condensation of mono halo sulfanilamide intermediate (7) with ethylene glycol in presence of base like sodium hydroxide and avoids the use of hazardous reagent like sodium metal with ethylene glycol, to prepare monosodium ethylene glycol prior to the condensation.

• In the final stages of synthesis contrary to the methods of prior art, ethylene glycol is used in the ratio of 5-10 moles per mole of the substrate and not as a solvent. This makes the purification of the final product much easier and also the effluents will contain less amounts of toxic ethylene glycol making it a more greener and esuriently process.
• Formation of lower concentration of impurities.
• Use of milder reagents when compared to the processes of prior art.
• Involves lesser number of steps, easy to perform and economically viable. The process can be scaled up to an industrial level.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: Illustrates the powder X-ray powder diffract gram of bosentan
Figure-2: Illustrates the IR spectrum of bosentan.
Figure-3: Illustrates the photographs of bosentan recorded on a microscope.
Detailed description of the invention:
The present invention relates to an improved process for the synthesis of bosentan monohydrate. The process involves the preparation of mono halo sulfanilamide intermediate (7) and its condensation with ethylene glycol in presence of base like sodium hydroxide to provide bosentan (1). The major focus of the invention was to develop a process for the synthesis of bosentan which involves lesser number of steps and milder reagents so that it can be adapted to a large scale process.
The process for the synthesis of bosentan encompasses the above features and comprises of the following steps;
a) Condensing diethyl 2-(2-methoxyphenoxy)malonate (2) with pyrimidine-2-carboximidamide hydrochloride (3), in the presence of a base in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4),
b) reacting 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4) with an halogenations agent in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine (5),

c) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine(5),
with 4-tert-butyl benzene sulfonamide (6) in presence of a base in a suitable non
polar aprotic solvent to obtain p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-
bipyrimidin]-4-yl]benzenesulfonamide or its salt (7),
d) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]
benzenesulfonamide or its salt (7) with ethylene glycol in the presence of a base and
a suitable aprotic solvent, with or without a phase transfer catalyst to obtain
bosentan.
In the step a) the condensation of diethyl 2-(2-methoxyphenoxy)malonate (2) with pyrimidine-2-carboximidamide hydrochloride (3) the base is selected from the group consisting of but is not limited to, hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithixim hydroxide; hydrides such as sodium hydride, potassiiun hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; preferably sodium methoxide. The solvent used is selected from a group of alcoholic solvents which include methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol preferably methanol.
In the step b) the halgenation of 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4) is carried out using a suitable halogenating agent selected from the group consisting of but is not limited to, thionyl chloride (SOCI2), phosphorus trichloride (PCI3), phosphorus pentachloride (PCI5), phosphorus oxychloride (POCI3), phosphorus tribromide (PBra), phosphorus pentabromide (PBrs) and the like, preferably phosphorus oxychloride in an aprotic solvent. The suitable aprotic solvent selected from the group consisting of but is not limited to, benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofiiran, preferably toluene
In step c) the coupling of the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine (5), with 4-tert-butyl benzene sulfonamide (6) the suitable bases that can be used in the reaction include but are not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the

like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably potassium carbonate. The suitable non polar aprotic solvent includes but are not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene
In the step d) bosentan is prepared by condensing p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7) directly with ethylene glycol (which is present in very low molar ratio), in the presence of a base and a suitable aprotic solvent. The base is selected from the group consisting of but not limited to hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide. The suitable aprotic solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyltetrahydrofiiran, preferably acetonitrile.
The phase transfer catalyst is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl diphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
The use of ethylene glycol in presence of a base in a suitable solvent not only reduced the number of steps but also the formation of impurities was arrested. The processes disclosed in prior art either utilize monoanion of ethylene glycol or monoprotected ethylene glycol.
The present aspect of the invention is represented in scheme-1


In another embodiment of the invention the process for the synthesis of bosentan comprises of the following steps;
a) Condensing diethyl 2-(2-methoxyphenoxy)malonate (2) with pyrimidine-2-
carboximidamide hydrochloride (3), in the presence of a base in a suitable solvent to
provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4),
b) reacting 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-456-dihydroxy pyrimidine (4)
with an halogenating agent in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-
(2'-pyrimidinyl)-4,6-dihalo pyrimidine (5), which on in-situ condensation with 4-
tert-butyl benzenesulfonamide (6) in presence of a base in a suitable non polar
aprotic solvent provided p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy) [2,2'-
bipyrimidin]-4-yl] benzenesulfonamide or its salt (7),
c) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]
benzenesulfonamide or its salt (7) with ethylene glycol in the presence of a base and a
suitable aprotic solvent, with or without a phase transfer catalyst to obtain bosentan.
In the present embodiment of the invention, 5-(2-methoxyphenoxy)-2-(2'-pyrimidyl)-4,6-dihalopyrimidine (5) formed in step b) is directly condensed in-situ with 4-tert-butylbenzenesulfonamide (6) to provide tert-butyl-N-[6-halo-5-(2-methoxy

phenoxy) [2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7), hence eliminating the need to isolate the dihalopyrimidine intermediate (5) which is a potent sensitizer and also decreasing a synthetic step.
The present aspect of the invention is represented in scheme-2

The present invention provides crystalline bosentan with an rod shaped morphology, which is highly pure, free flowing solid and easy to handle during formulation as an active pharmaceutical ingredient. It has a greater advantage over the prior art forms.
The impurity formed in the present invention which was isolated and characterized was p-tert-butyl-N"[6-(methoxy)-5-(2-methoxyphenoxy)[252'"bipyrimidin]-4-yl] benzene sulfonamide (8).


The above impurity is formed due to the presence of methanol traces in the reaction medium. The above impurity was synthesized (as illustrated in Scheme-3) and characterized by its spectral data.

GENERAL EXPERIMENTAL CONDITIONS
The IR spectrum of impurity was recorded on TEC Nicolet 380 model FT-IR as KBr pellet.
The mass spectrum of impurity was recorded on positive AL MS by mass spectrometer.
The ^H NMR data was recorded in CDCI3 solvent on Advances 300 MHz spectrometer using TMS as intemal standard.
Analysis of particle size distribution of bosentan: A Malvern laser diffraction instrument was used to characterize the particle size distribution of bosentan. Instrument model: Malvern Mastersizer 2000 Technique used: Wet method Instrument parameters:
i) Material RI: 1.65
ii) Dispersant RI: 1.468
iii) Despersant: Light liquid paraffin
iv) Sensitivity: Normal
v) Particle shape : Irregular
vi) Stirrer speed : 2600 rpm

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC): METHOD OF ANALYSIS
Chromatographic conditions:
Apparatus : A liquid chromatograph is equipped with variable wave length UV
detector.
Column : Inertsil CDS 3V, 250 X 4, 6mm, 5|im or Equivalent.
Flow rate : 1.0 ml/min.
Wave length : 220 nm.
Temperature : 25° C
Load : 20

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example 1: 5-(2-methoxyphenoxy)-2-(2'-pyrimidmyl)-4,6-dihydroxy pyrimidine (4)
To a solution of diethyl 2-(2-methoxyphenoxy)malonate (2) (289 g) in methanol (400 ml) sodium methoxide (100 ml) was added slowly within 20 min and then stirred for 30 min. A solution of pyrimidine-2-carboximidamide hydrochloride (3) (100 g) dissolved in methanol (750 ml) was added to the reaction mixture and stirred at 25- 30°C for 25 hrs. The reaction mixture was concentrated in vacuum to get a solid residue. The obtained residue was dissolved in 1000 ml water and pH was adjusted to 5-6 with dilute HCl. The precipitated product was filtered, washed with water and dried at 50^C. The title compound was obtained as a pale yellowish powder. Yield: 190 g
Example 2: Preparation of 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dichloro pyrimidine (5)
To 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4) (100 g), POCI3 (500 ml) was added. Heated the reaction mixture to 90°C and stirred for 30 min. The temperature of the reaction mixture was raised to 105°C and was stirred for 8 hrs. The reaction mixture was cooled to 60°C and concentrated to obtain a residue. The reaction mixture was quenched with ice water and toluene was added to it. The pH was adjusted to 8-9 with 30% sodium hydroxide solution. The organic and the aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layers were combined, washed with water and dried. The solvent was distilled off to provide the title compound as a solid. Yield: 96 g Melting range: 138-140

Example 3: p-tert-butyl-N-[6-chloro-5-(2-inethoxyphenoxy)[2,2*-bipyrimidin]-4-yl] benzenesulfonamide potassium salt (7)
To a solution of 4-tert-butyl benzene sulfonamide (6) (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50°C. A solution of 5-(2-methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro pyrimidine (5) (60 g) in toluene (1200 ml) was added slowly to the reaction mixture and it was refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C.The solid obtained was filtered and made slurry in water. The solid was filtered, washed with water and dried. Yield: 90 g
Example 4: p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzenesulfonamide potassium salt (7)
To 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4) (100 g), POCI3 (500 ml) was added. Heated the reaction mixture to 90°C and stirred for 30 min. The temperature of the reaction mixture was raised to 105°C and was stirred for 8 hrs. The reaction mixture was cooled to 60°C and concentrated to obtain a residue. The reaction mixture was quenched with ice water and toluene(1200 ml) was added to it. The pH was adjusted to 8-9 with 30% sodium hydroxide solution. The organic and the aqueous layers were separated. The aqueous layer was extracted with toluene (200 ml). The organic layers were combined, washed with water and dried. The solvent was concentrated to 1200 ml and a solution of 4-tert-butyl benzene sulfonamide (6) (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50°C. The reaction mixture was heated to refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C.The solid obtained was filtered and made slurry in water. The solid was filtered, washed with water and dried. Yield: 92 g
Example 5: Preparation of bosentan.
A mixture of ethylene glycol (5.5 g), acetonitrile (130 ml), and sodium hydroxide (2.8 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert-

butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonami potassium salt (7) (5 g) was a added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25°C, quenched with water and the pH was adjusted to 2-3 with IN HCL Toluene was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (15 ml) and heated to 60-65°C and stirred for 30 min. Water (15 ml) was added drop wise to the reaction mixture, then cooled to 25 °C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1:1). The compound was air dried to provide the title compound. Yield: 4.2 g MR: 138-140°C HPLC Purity: 99.70 % Water content: 3.2 % (w/w)
Particle size distribution: D(0.1):9.677; D(0.5):37,410; D(0.9): 122.534; D(1.00):269.50. (Bosentan prepared above was Micronized to provide bosentan with mean particle size in the range of below 20 microns, which on further mercerization provided bosentan with a mean particle size in the range of below 10 microns.)
Example 6: Preparation of bosentan.
A mixture of ethylene glycol (5.5 g), acetonitrile (130 ml), sodium hydroxide (2.8 g) and tetra butyl ammonium bromide (0.5 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt (7) (5 g) was a added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25°C, quenched with water and the pH was adjusted to 2-3 with IN HCL Toluene was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (15 ml) and heated to 60-65°Cand

stirred for 30 min. Water (15 ml) was added drop wise to the reaction mixture, then cooled to 25 °C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1:1). The compound was air dried to provide the title compound. Yield: 4.0 g
Example 7: Preparation of bosentan.
A mixture of ethylene glycol (6 g), acetonitrile (30 ml), and potassium carbonate (5 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert-butyl-N-[6-chlorO"5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt (7) (500 mg) was added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25°C, quenched with water and the pH was adjusted to 2-3 with IN HCl. Toluene (20 ml) was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene (10 ml). The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (2ml) and heated to 60-65 °Cand stirred for 30 min. Water (3 ml) was added drop wise to the reaction mixture, then cooled to 25°C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1:1). The compound was air dried to provide the title compound. Yield: 250 mg
Example 8: Preparation of bosentan sodium.
To a solution of bosentan (3 g) in ethanol (15 ml), 30% sodium hydroxide was added drop wise at 25-30°C and stirred the solution slowly until a solid was formed. The reaction mixture was stirred for one hour at 25-30°C. Filtered the solid formed and washed with ethanol. The solid was dried to obtain the title compound. Yield: 1.5 g Water content: 2.7%; Assay: 95.66 % MR:215-218°C

Example 9: Preparation of bosentan potassium.
To a solution of bosentan (3 g) in ethanol (15 ml), 30% potassixim hydroxide was added drop wise at 25-30°C and stirred the solution slowly until a solid was formed. The reaction mixture was stirred for one hour at 25-30°C. Filtered the solid formed and washed with ethanol. The solid was dried to obtain the title compound. Yield: 1.2 g Water content: 3.5 %; Assay: 100% MR:218-220°C
Example 10: Preparation of p-tert-butyl-N-[6-(methoxy)-5-(2-methoxyphenoxy) [2,2*-bipyrimidin]-4-yl] benzenesulfonamide salt (8)( impurity).
To a solution of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt (7) (0.5 g) in toluene (8 ml), sodium hydroxide (0,07 g) and methanol (2 ml) was added and the reaction mixture was heated to 50- 55°C and stirred for 6 hrs. Cooled the reaction mixture to 10-15°C and adjusted the pH to 3-4 with hydrochloric acid. The reaction mixture was extracted with dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulfate and distilled off to obtain the title compound as a solid. Yield: 0.4 g
Mass spectrum: [M^+1] Peak at m/z 522 IR (cm*^): 3420 (NH str); 1375 (S02Str).
'H NMR (5): 1.25 (s, 9H); 3.78 (s, 3H), 3.83(s, 3H); 6.55-7.08 (m, 4H), 7.41-7.45 (m, 3H); 8.25-8.27 (d, 2H); 9.09-9.13 (d, 2H); 11.4 (br, IH)

We Claim:
1. The process for the synthesis of bosentan comprising of the following steps;
a) Condensing diethyl 2-(2-methoxyphenoxy)malonate (2)

With pyrimidine-2-carboximidamide hydrochloride (3),

in the presence of a base in a suitable solvent to provide 5-(2-methoxyphenoxy)-2- (2'pyrimidinyl)-4,6-dihydroxy pyrimidine (4),

b) Reacting 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine (4)
with a halogen ting agent in a suitable solvent to provide 5-(2-methoxyphenoxy)-
2-(2'-pyrimidinyl)-4,6-dihalo pyrimidine (5),

c) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine(5)5
with 4-tert-butyl benzenesulfonamide (6),


in presence of a base in a suitable non polar aprotic solvent to obtain p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy) [2,2*-bipyrimidin]-4-yl] benzene sulfonamide or its salt (7),

d) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7) with ethylene glycol in the presence of a base and a suitable aprotic solvent, with or without a phase transfer catalyst to obtain bosentan.
2. A process for the preparation of bosentan comprising of the condensation of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7) with ethylene glycol, in presence of a base and a suitable aprotic solvent with or without a phase transfer catalyst to provide bosentan.
3. The process of claim 2 wherein the base is selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and ethoxide; the suitable aprotic solvent is selected from a group consisting of benzene, toluene, xylene, acetonitrile, tetrahydrofuran and 2-methyltetrahydrofuran and the phase transfer catalyst is selected from a group consisting of tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride.

tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl diphenyl phosphine bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
4. The use of alkali or alkaline earth metal hydroxides or their carbonates in the
condensation of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-
yljbenzene sulfonamide or its salt (7) with ethylene glycol to provide bosentan.
5. The use of sodium hydroxide in the condensation of p-tert-butyl-N-[6-halo-5-(2-
methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide or its salt (7) with
ethylene glycol to provide bosentan.
6. The use of acetonitrile as a solvent in the condensation of p-tert-butyl-N-[6-halo-5-(2-
methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt (7) with
ethylene glycol, to provide bosentan.
7. A process for the synthesis of bosentan comprising of the following steps;
a) Condensing diethyl 2-(2-methoxyphenoxy)malonate (2)



b) reacting 5-(2-methoxyphenoxy)-2-(2'pyrimidinyl)-456-dihydroxy pyrimidine (4)
with a halogenating agent in a suitable solvent to provide 5-(2-methoxyphenoxy)-
2-(2'-pyrimidinyl)-456-dihalo pyrimidine (5),

wherein X is a halogen which on in-situ condensation with 4-tert-butyl benzene sulfonamide (6),

in presence of a base in a suitable non polar aprotic solvent to obtain p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzenesulfon-amide or its salt (7),

wherein M is a hydrogen or alkalis or alkaline earth metal ion X is a halogen
c) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]
benzenesulfonamide or its salt (7) with ethylene glycol in the presence of a base
and a suitable aprotic solvent, with or without a phase transfer catalyst to obtain
bosentan.

8. A compound p4ert-butyl-N-[6-(methoxy)-5-(2-methoxyphenoxy)[2,2*-bipyrimidin]
-4-yl] benzenesulfonamide (8).

9. Bosentan containing the impurity p-tert-butyl-N-[6"(methoxy)-5-(2-methoxy
phenoxy) [2,2*-bipyrimidin]-4-yl] benzene sulfonamide (8), in a concentration
less than 0.1 % area by HPLC.
10. Substantially pure bosentan having a purity of 99.70 % area by HPLC.
11. Bosentan has a mean particle size in the range of 30-60 microns and D (v 0.9) in the range of 80-140 microns.
12. Bosentan having a morphology as shown in figure-3.