HOVEL PROCESS FOR THE PREPARATION OF BOSENTAN
Field of Invention:
The present invention is directed to a novel process for preparing bosentan. Bosentan is chemically known as 4-( 1,1 -Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide 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 ETB 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. This patent also disclosed the method for preparing these compounds. One of the methods involves the condensation of diethyl (2-methoxyphenoxy) malonate with pyrimidine-2-carboxyarmdine in presence of sodium methoxide, which is converted into dichloro derivative by treatment with phosphorus oxychloride at reflux temperature. 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 pharmaceutical^ 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. In the final stages diisopropyl ether is used for purification by recrystallization 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.

The present invention overcomes the major disadvantage mentioned above. In the first aspect of the present invention, in the final stage 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2, 2'-bipyrimidin-4-yI) benzenesulfonamide is reduced to provide bosentan, in which there is no possibility of formation of the undesired 1,2-diheteroethylene bis-sulfonamides. In the second aspect in the final stage p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide is reacted with 2-haloethan-l-ol to provide bosentan. In this process also the formation of undesired 1,2-diheteroethylene bis-sulfonamides is controlled.
The present invention avoids the use of ethylene glycol which makes this process facile, easy to workup and leads to less contamination.
The present invention overcomes the disadvantages of the prior art processes. It is easier to perform as it 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.
Brief Description of the Invention:
The present invention relates to a novel process for the synthesis of bosentan. Bosentan is chemically known as 4-(l,l-Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yI]benzenesuIfonamide monohydrate, having structural formula-1.

The first aspect of the present invention provides a novel method for the synthesis of bosentan which comprises of the reaction of 6-halosuIfonamide compound of formuIa-2 with a substituted allyl alcohol, compound of formula-3 (or) by the reaction of 6-hydroxy sulfonamide derivative of formula-4, with a substituted allyl halide, compound of formula-5 in presence of base in a suitable solvent, to provide a substituted 6-allyIoxy sulfonamide derivative of formula-6. The compound of formula-6 on treatment with hydroxylating agent provides a diol compound, which on subsequent oxidation in-situ provided an aldehyde derivative of formula-7.

The compound of formula-7 on reduction with a suitable reducing agent provides bosentan, compound of formula-1.
The second aspect of the present invention relates to a novel process for the synthesis of bosentan. The process involves the reaction of mono halo sulfonamide derivative of formula-2 (or) the reaction of alkoxy-sulfonamide derivative of formula-8, with alkali or alkaline metal base in the presence of suitable solvent provides a hydroxy intermediate of formula-4, which on reaction witti 2-halo ethan-1-ol in the presence of suitable base gives bosentan, compound of formula-1.
In the third aspect of the present invention provides an improved method for the synthesis of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide, intermediate of bosentan, compound of formula-2a. It comprises of the reaction of 4,6-dichIoro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, compound of formula-9, with 4-tert-butylbenzene -sulfonamide in the presence of potassium carbonate and a suitable aprotic solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzenesulfonamide potassium salt, compound of formula-10, which is isolated as a solid, which on hydrolysis with aqueous hydrochloric acid provides p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesuIfonamide, compound of formula-2a as a solid with high purity.
Advantages of the Present Invention:
• Provides a novel process which avoids the formation of dimer impurity and therefore having high purity.
• Eco-friendly and cost effective process.
Brief Description of Drawing:
Figure-l: Illustrates the X-ray powder diffraction pattern of potassium salt of bosentan
(formula-10)
Figure-2: Illustrates the Infrared spectrum of potassium salt of bosentan (formula-10)
Figure-3: Illustrates the DSC chromatogram of potassium salt of bosentan (formula-10)
Figure-4: Illustrates the HPLC chromatogram of potassium salt of bosentan (formula-10)
Figure-5: Illustrates the DSC chromatogram of bosentan

Detailed description of the invention:
The present invention relates to a novel process for the synthesis of bosentan. Bosentan is
chemically known as 4-(l,l-dimethylethyI)-N-[6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yI]benzenesulfonamide monohydrate, having structural formula-1.

Accordingly the first aspect of the invention provides a novel method for the synthesis of bosentan which comprises of the following steps;
a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-
sulfonamide compuond of formula-2, with a substituted allylalcohol, compound of
formula-3, in the presence of base and a suitable solvent, with or without a phase transfer
catalyst, to provide p-tert-butyI-N-[6-(substiruted allyloxy)-5-(2-methoxyphenoxy)[2,2'-
bipyrimidin]-4-yl]benzene-sulfonamide, compound of formula-6, (OR)
by reacting p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]
benzenesulfonamide derivative of formula-4, with a substituted allylhalide, compound of formula-5, in the presence of base and a suitable solvent, with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy)[2)2'-bipyrimidin]-4-yl] benzenesulfonamide, compound of formula-6; wherein halogen is either chlorine or bromine;
b) treating p-tert-bntyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy){2,2'-bipyrimidin)-4-yljbenzenesulfonamide, compound of formula-6, with a hydroxylating agent provides dihydroxy derivative, which upon subsequent oxidation in-situ, provides an aldehyde derivative 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2)2'-bipyrimidin-4-yI) benzenesulfonamide, compound of formula-7,
c) treating 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide, compound of formula-7, with a reducing agent in a suitable solvent to obtain bosentan, compound of formula -1.

In the step a) the reaction of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yI]benzenesulfonamide, compound of formula-2, with a substituted allyl alcohol, compound of formula-3, or p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-4, with a substituted allyl halide, compound of formula-5, is carried out in the presence of a base selected from a group which may include but is 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 sodium hydroxide and in the suitable solvent selected from a group which may include but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-memyltetrahydrofuran and acetonitirle, preferably acetonitrile to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-mewoxyphenoxy)[2,2'-bipyTimidin]-4-yl] benzene sulfonamide compound of formula-6 . The phase transfer catalyst which can be used is selected from the group consisting of but is not limited to terra 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 triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. (Or)
the reaction of p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide, compound of formula-4, with a substituted allyl halide, compound of formula-5, is carried out in the presence of a base selected from a group which may include but is 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 sodium hydroxide and in the suitable solvent selected from a group which may include but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitirle, preferably acetonitrile to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-6 . The phase transfer catalyst which can be used is selected from the group consisting of but is 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 triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
In the step b) p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy)[2,2'-bi pyrimidin]-4-yl]benzenesuffonamide derivative of formula-6, on treatment with hydroxylating agents like OSO4 in presence of H2O2 or N-methylmorpholme N-oxide or KMnC>4 or PhC02Ag/l2 in a suitable solvents like methanol, ethanol, propanol, isopropanol and the like, preferably tert-butyl alcohol provides diol derivative, which on subsequent oxidiation in-situ, in the presence of oxidizing agents like NaIC>4 or Pd(OAc)4 provides 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-7.
In step c) 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2, 2'-bipyrimidin-4-yl) benzenesulfonamide, compound of formula-7, is reduced with a reducing agent selected from a group which includes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodium dihydro-bis-(2-methoxyethoxy)aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride in a suitable alcoholic solvent selected from the group which may include alcohols like methanol, ethanol, propanol, isopropanol and the like to obtain, bosentan, compound of formula-1. The present aspect of the invention is represented in scheme-1.
The second aspect of the present invention relates to a novel route for the synthesis of bosentan. This process for the synthesis of bosentan comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene¬sulfonamide, compound of formula-2 with a base, in a suitable solvent and with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesuIfonamide, compound of formula-4, (or)
Reacting p-tert-butyl-N-[6-alkoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide derivative of formuIa-8, with a base, in a suitable solvent and with or without a

phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide, compound of formula-4,
wherein alkyl moiety present in the alkoxy group may be Ci-Ce alkyl group which may be a straight or branched chain, b) p4ert-butyl-N-[6-(hydroxy)-5-(2-methoxypherioxy)[2,2,-bipyrirnidin]-4-yl]berizene
sulfonamide compound of formula-4, upon treating with 2-halo-ethan-l-oI, wherein halogen is either chlorine or bromine; in presence of suitable base, an aprotic solvent and with or without a phase transfer catalyst, provides bosentan, compound of formula-1.
In the step a) the suitable bases that can be used in the reaction is selected from a group which includes but is 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 sodium hydroxide. The suitable solvent which is used is selected from a group which includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, ethylene glycol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran. The phase transfer catalyst is selected from the group consisting of but is 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 triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
In the step b) the compound of formula-1 is obtained by the reaction of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide compound of formula-4 with 2-halo-ethan-l-ol, in presence of suitable base selected from a group which includes but is 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 sodium carbonate. The phase transfer catalyst which can be used is selected from the group consisting of but is 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 trimethyi ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. The present aspect of the invention is represented in scheme-2.
In the third aspect of the invention provides an improved method for the synthesis of an intermediate of bosentan, i.e. p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide, compound of formu!a-2a comprises of the following steps; a) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine compound of formula-9 with 4-terbutyl benzenesulfonamide in the presence of potassium carbonate and a suitable aprotic solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide potassium salt, compound of forniula-10 as a solid, b) reacting potassium salt of p-tert-butyI-N-[6-chIoro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yI]benzenesulfonamide, compound of formula-10 in presence of an aqueous hydrochloric acid provides p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide, compound of formula-2a as a solid with high purity.
In step a) the suitable solvent is selected from the group which may include but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrah.ydrofaran, dimethylformamide, dimethylsulfoxide, to provide p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide potassium salt compound of formula-10 as a solid.
The phase transfer catalyst used in step a) is selected from the group consisting of but is 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 trimethyi ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl

phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide, and lithium iodide.
The present invention provides highly pure solid compounds of freebase, compound of formuIa-2a as well as 6-chloro benzene sulfonamide potassium salt, compound of formula-10.
US patent 6,136,971 discloses the said intermediate, but it is not isolated and is used in the next step as a suspension in toluene. US patent 5,292,740 also mentions the formation of potassium salt of the above intermediate in the synthesis of bosentan and its analogues but is silent about its isolation and its nature. In the present invention the p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide potassium salt compound of formula-10, was isolated as a highly pure solid which when used for the preparation of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyramidin]-4-yl]benzene sulfonamide, compound of formula-2a (freebase) provided the product with high purity >99%. The present aspect of the invention is represented in scheme-3




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: Preparation of p-tert-butyl-N-[6-(allyloxy)-5-(2-methoxypbenoxy)[2,2,-
bipyrimidin]-4-yl] benzenesulfonamide (formula- 6).
To a solution of prop-2-en-l-ol (51.4 grams) in acetonitrile (350 ml), sodium hydroxide (14.18 grams) was added and heated to 80-85°C for 4 hrs. The reaction mixture was cooled to 25-30°C and p-tert-butyl-N-[6-halo-5-(2-niethoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide (50 grams) was added followed by heating to 80-85°C for 14 hrs. Then water (600 ml) was added and the pH was adjusted to 2.0 by using hydrochloric acid. The reaction mixture was maintained at 27°C for 40 min, the solid formed was filtered and washed with water. The compound was dried for 2 hrs at 60-65°C. Yield: 43 grams (89%)
Example-2: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2^2'-bipyrimidin-4-yl) benzenesulfonamide (formula-7).
To a solution of p-tert-butyl-N-[6-(aIIyloxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzenesulfonamide (25 grams) in methanol (350 ml), OsO^ (0.1 gm), H2O2 (75 ml), and water (200 ml) were added. The reaction mixture was stirred for 24 hrs at 25-35°C. The solvent was distilled off from reaction mixture and dichloromethane was added and stirred for 15 min. The organic layer was separated and washed with water. The solvent was distilled off from filtrate and residue dissolved in acetone. Aqueous sodium periodate was added to the reaction mixture and stirred for 7 hrs at 25-30°C temperature and filtered. The solvent was distilled off from the filtrate and the residue, extracted with chloroform. The organic layer was washed with water, the solvent was distilled off to provide the title compound as a solid. Yield: 20 grams (80%).
Example-3: Preparation of bosentan (formula-1).
A solution of 4-tert-butyl-N-(5-(2-memoxyphenoxy)-6<2-oxoemoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide (formula-7) (10 grams) in methanol (100 ml) was cooled to 0-5°C and

sodium borohydride (0.69 grams) was slowly added in portions. Stirred the reaction mixture for 2 hr.The reaction mixture was poured into crushed ice and the pH adjusted to 2.0 with HC1. The solid precipitated was filtered, washed with water and dried. Yield: 8 grams (77 %).
ExampIe-4: Preparation of p-tert-buty!-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yI]benzenesuIfonamide (formula-4).
To a solution of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide (formuIa-2) (50 grams) in ethylene glycol (329.7 grains), sodium hydroxide (10.6 grams) was added and heated to 160-165°C for 10 hours. The reaction was quenched with water and the pH was adjusted to 2.0 with hydrochloric acid. The reaction mixture was stirred at room temperature for 40 min.The precipitated solid was filtered and washed with water. The compound is dried at 70-75°C for 10 hours. Yield: 41 grams (91%)
Example-5: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzenesulfonamide (formula-4).
To a solution of p-tert-butyl-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide (formula-8a) (50 grams) in ethylene glycol (329.7 grams), sodium hydroxide (10.6 grams) was added and heated to 160-165°C for 10 hours. The reaction was quenched with water and the pH was adjusted to 2.0 with hydrochloric acid. The reaction mixture was stirred at room temperature for 40 min. The precipitated solid was filtered and washed with water. The compound is dried at 70-75°C for 10 hours. Yield: 42 grams (93%)
Example-6: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzenesulfonamide (formula-4).
To a solution of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2s2'-bipyrimidin]-4-yl]benzene-sulfonamide (formula-2) (50 grams) in toluene (500 ml), sodium hydroxide (35 grams), tetra butyl ammonium bromide ( 2.8 grams) was added and heated to 105-110°C for 16 hours. The reaction was quenched with water. The reaction mixture was stirred at room

temperature for 40 min. The precipitated solid was filtered and washed with water. The compound is dried at 70°-75°C for 10 hours. Yield: 45 grams (93%)
Example-7: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide (formuIa-4).
To a solution of p-tert-butyl-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide (formula-Sa) (50 grams) in toluene (500 ml), sodium hydroxide (57.5 grams), tetra butyl ammonium bromide (2.8 grams) was added and heated to 105-110°C for 18 hours. The reaction was quenched with water. The reaction mixture was stirred at room temperature for 40 min. The precipitated solid was filtered and washed with water. The compound is dried at 70-75°C for 10 hours. Yield: 39 grams (80 %)
Example-8: Preparation of bosentan (formula-l).
To a solution of p-tert-butyI-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide (formula-4) (38.5 grams) in dimethylformamide (450 ml), sodium carbonate (32.16 grams) was added and heated to 110-115°C for 4 hrs. 2- Chloroethanol (54.96 grams) (50 ml) was added to the reaction mixture and stirred for 16 hrs. Water was added to the reaction mixture and the pH was adjusted to 2 with hydrochloric acid. Dichloromethane (700 ml) was added to the reaction mixture. The aqueous and organic layers were separated. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off from organic layer and residue was taken in methanol (150 ml) and stirred for 30 min. Water (200 ml) was added to the reaction mixture and stirred for 4 hrs. The precipitated solid was filtered, washed with water and air dried. Yield: 36 grams (82.5 %)
Example-9: Preparation of p-tert-butyl-N-[6-chIoro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide potassium salt (formula-10)
To a solution of 4-tert-butyl benzene sulfonamide (61.3 grams) in toluene (1500 ml), potassium carbonate (77.93 grams) and tetra butyl ammonium bromide (2.77 grams) was added

and the reaction mixture was heated to 50°C. A solution of 5-(2-methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro pyrimidine (formula-9) (100 grams) in toluene (1500 ml) was added slowly to the reaction mixture and it was refluxed 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 followed by acetonitrile and dried. Yield: 116 grams, HPLC purity: 99.5%, MR: 202-205°C.
Example-10: Preparation of p-tert-butyI-N-[6-chloro-5-(2-methoxyphenoxy)[2^'-bipyrimidin]-4-yI]benzenesu!fonamide(formula-2a).
Water (100 ml) was added to potassium salt of p-tert-butyI-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide (50 grams) and the pH of the mixture was adjusted to 2 with hydrochloric acid and stirred for Ihr. The obtained solid is filtered off and washed with acetonitrile. Dried the solid to get the title compound. Yield: 42 grams

We Claim:
1. A process for the synthesis of bosentan which comprises of;
a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene
sulfonamide compound of formula (2)

Wherein halogen (X) is either chlorine or bromine, with substituted allyl alcohol of formula-3,
Formula-3
wherein R' = C1-C8 branched/straight chain alkyl group or an aryl group,
in the presence of base and a suitable solvent with or without phase transfer catalyst to
provide p-tert-butyl-N-[6-(allyloxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yi]
benzene sulfonamide, compound of formula- 6,

b) treating p-tert-butyl-N-[6-(substitutedallyloxy)-5-(2-mefhoxyphenoxy){2,2'-bipyrimidin)-
4-yl]benzene sulfonamide, compound of formula-6 with an hydroxylating agent provides
dihydroxy derivative, which on subsequent oxidation in-situ, provides the aldehyde
derivative 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-
yl)benzene sulfonamide compound of formula-7,


c) treating 4-tert-butyI-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2, 2'-bipyrimidin-4-yl) benzene sulfonamide, compound of formula-7 with a reducing agent in suitable solvent to obtain bosentan, compound of formula -1.

2. A process for the synthesis of bosentan which comprises of;
a) by reacting p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yI] benzene sulfonamide compound of formula-4

with a substituted allyl halide compound of formula-5

wherein R' =C1-C8 branched/ straight chain aikyl group or an aryl group, and X is chlorine or bromine,
17

in the presence of base and a suitable solvent with or without phase transfer catalyst to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide, compound of fonnula-6,

wherein R' = Ci-Cs branched/ straight chain alkyl group or an aryl group,
b) treating p-tert-butyl-N-[6-(substitutedallyIoxy)-5-(2-methoxyphenoxy){2,2'-bipyrimidin)
-4-yr]benzenesulfonamide, compound of formula-6, with an hydroxylating agent provides
dihydroxy derivative, which on subsequent oxidation in-situ, provides the aldehyde
derivative 4-tert-butyI-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)
benzenesulfonamide compound of formula-7,

c) treating 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)
benzenesulfonamide, compound of formula-7 with a reducing agent in suitable solvent to
obtain bosentan, compound of formula -1.


The process of claims 1 and 2, wherein in the base is selected from the group which may include but is 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.
The process of claims 1 and 2, wherein in the suitable solvent selected from a group which may include but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile.
The process of claims 1 and 2, wherein in the phase transfer catalyst is selected from the group consisting of but is not limited to terra butyl ammonium bromide, terra propyl ammonium bromide, tributyl benzyl ammonium bromide, terra octyl ammonium bromide, terra butyl ammonium iodide, terra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
The process of claim 1 and wherein in the hydroxylating agent is selected from OSO4 in presence of H2O2 or N-methyl morpholine N-oxide or KMn04 or PhCC>2Ag/l2 in a suitable ;olvents like methanol, ethanol, propanol, isopropanol and the like. And oxidizing agent is elected from NalCU or Pd(OAc)4-
"he process of claims 1 and 2, wherein in the reducing agent is selected from a group which acludes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride ;'L-selectride"), sodiumdihydro-bis-(2-methoxyethoxy)aluminate (Vitride), bis diisobutyi luminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride 1 a suitable alcoholic solvent selected from the group which may include alcohols like lethanol, ethanol, propanol, isopropanol and the like.





he presence of base, a suitable solvent and with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-^Ibenzenesulfonamide, compound of formula-4,
)-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene
lulfonamide compound of formula-4., upon treating with 2-haIo-ethan-l-oL wherein
halogen is either chlorine or bromine;
in presence of suitable base and an aprotic solvent with or without a phase transfer
catalyst, provides bosentan, compound of formula -1.
13. The process of claimsl6 to 20, wherein in the base used is selected from the group which may include but is 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.
14. The process of claims 16 step b), claim 18 and claim 19 step b), the base used is sodium carbonate.
15. The process of claims 16 to 20 wherein the suitable solvent which is used is selected from a group which includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, ethylene glycol, dimethylformamide, dimethylsulfoxide, and, tetrahydrofuran.
16. An improved process for the preparation of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide, compound of formula-2a which comprises of the following steps;
a) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine compound of formula-9



17. Crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt, compound of formula-10, characterized by any one of the following,
a) It's XRD wherein peaks were observed at about 4.2, 8.3,9.6,15.6,16.3,18.3,19.3,20.5,
21.0,22.1,26.0,27.5, and 28.4 ± 0.2 degrees two theta.
b) It's IR wherein peaks were observed at 3467.4, 3062.8, 2960.9, 1662.9, 1591.9,1551.4,
1501.0, 1448.5, 1249.3, 858.7, 795.0, 719.8, 694.4, 586.0, and 540.6 cm"1.
c) It's DSC thermo gram having endothermic peak at about 201.14°C and exothermic peak
at about 306.17°C.