Field of Invention:
The present invention relates to an improved process for the preparation of 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 the following structural formula-1.

Formula-1 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.
Background of the Invention:
Bosentan and process for its preparation have been first disclosed in US patent No. 5,292,740. The process disclosed in this patent involves the condensation of diethyl (2-methoxyphenoxy) malonate with pyrimidine-2-carboxyamidine in presence of sodium methoxide, 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 perform at a large scale in an industrial process. Moreover the said patent involves the usage of a halogenated solvent e.g., methylene chloride, during the isolation of pyrimidine dihalide. It is difficult and expensive to dispose off the halogenated solvents properly, thus leading to added cost. 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.
Like any chemical compound, bosentan monohydrate can contain extraneous compounds or impurities that can come from many sources. Process impurities which are present in the active pharmaceutical ingredient include, unreacted starting materials, chemical derivatives of impurities contained in the starting materials, synthetic by-products etc. Impurities in an active pharmaceutical ingredient may also arise from degradation of the active pharmaceutical ingredient itself, which is related to the stability of the pure active pharmaceutical ingredient during storage.
Impurities in bosentan or any active pharmaceutical ingredient are undesirable, and in extreme cases, might even be harmful to a patient being treating with a dosage form of the active pharmaceutical ingredient in which a sufficient amount of impurities are present. Furthermore, the undesired enantiomeric impurities reduce the sufficient level of active pharmaceutical ingredient present in the pharmaceutical composition.
In addition to stability, which is factor in the shelf life of the active pharmaceutical ingredient, the purity of the active pharmaceutical ingredient in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidelines for active pharmaceutical ingredient manufacturers requires that process impurities be maintained below set limits by

specifying the quality raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during the preparation process, it should be analyzed for the purity by HPLC or TLC analysis to determine if it is desirable for continue the process or need to purified further to continue the process especially for use in a pharmaceutical product. The active pharmaceutical ingredient need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather the purity standards are set with the intention of ensuring that an active pharmaceutical ingredient is as free of impurities as possible, and thus, is as safe as possible for clinical use.
It is known to a person skilled in art that an impurity can be controlled by knowing the structure of the impurity, the process parameters, and the interaction of the impurity with other reagents, solvents, intermediates etc. as well as the final pharmaceutical drug.
When we involve in the preparation of bosentan as per the prior art process, in some of the experiments it was observed that an impurity at 0.8 RRT was present in substantial proportions. This impurity could not be removed from the final product by the conventional methods of purification like crystallization etc due to its similarity in structure, as well as physical properties when compared with bosentan. So in order to develop a technique to remove/control this particular impurity, we isolated the same using column chromatography and characterized the obtained impurity compound. The impurity was found to be 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-6 (herein designated as "isopropyl impurity"). Hence there is a need to synthesize and control the impurity 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide in bosentan.

Organic Process Research & Development 2002, 6, 120-124 disclosed that the bosentan prepared by the prior art process contains high levels of dimer impurity and pyrimidinone impurity and the same can be reduced by the recrystallisation of bosentan from methanol-isopropyl acetate, followed by ethanol-water purification to provide bosentan with purity of 99.3% by HPLC. The dimer and pyrimidinone impurities were represented by the following structural formula.

The said article disclosed the second generation process for the preparation of high pure bosentan through monoprotected ethylene glycol providing bosentan with the purity of 99.70 % containing low level of dimer and pyrimidinone impurities.
The prior art data base article IPCOM000185691 also disclosed the process for the crystallization of bosentan from a mixture of methanol and isopropyl acetate and provides the PXRD of obtained bosentan, which is designated as form X. However the purity of the bosentan obtained by the above processes is not satisfactory. Hence there is a need in art to develop an improved process which can provide better yields and high purity and which can be performed at an industrial scale.
Our earlier International publication WO 2009/095933 disclosed the usage of all type of bases in the condensation reaction between 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide with ethylene glycol.
The present invention provides an improved process for the preparation of bosentan which avoids the above mentioned prior art problems as well as provides the process for the preparation and control of isopropyl impurity.

Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of bosentan compound of formula-1, which comprises of reacting the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-2a with ethylene glycol compound of formula-3 in the presence of a alkoxide base in a suitable solvent to provide bosentan compound of formula-1.
The second aspect of the present invention is to provide a process for the preparation of high pure bosentan compound of formula-1 from suitable solvents in presence of water, particularly to reduce the amount of dimer impurity.
The third aspect of the present invention is to provide preparation, isolation, and characterization of an "Isopropyl impurity" and its alkali metal salt as well as process for its control in the preparation of bosentan.
The fourth aspect of the present invention is to provide an improved process for the preparation of highly pure bosentan substantially free of isopropyl impurity which comprises of;
a) Condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4, with 4-tert-butylbenzene sulfonamide having less than 0.15% of 4-isopropylbenzene sulfonamide, in presence of a base in a suitable non polar aprotic solvent to obtain 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-2,
b) reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-2 with ethylene glycol compound of formula-3 in the presence a suitable base in a suitable solvent to provide bosentan compound of formula-1,
c) purifying the obtained bosentan compound of formula-1 using a suitable solvent to provide pure bosentan compound of formula-1.

Advantages of the Present Invention:
• The major advantage of the process is that it involves the usage of base like sodium tert-butoxide avoids the use of pyrophoric reagent like sodium metal with ethylene glycol, to prepare monosodium ethylene glycol prior to the condensation.
• Preparation, isolation, characterization and control of the "Isopropyl impurity".
• Use of milder reagents when compared to the processes of prior art.
• Eco-friendly and economically viable process
• Bosentan free of 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide (isopropyl impurity) or its alkali metal salt & dimer impurity.
Detailed description of the invention:
The present invention relates to an improved process for the preparation of bosentan monohydrate compound of formula-1.

The first aspect of the present invention provides an improved process for the preparation of bosentan compound of formula-1, which comprises of reacting the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-2
Formula-2

Wherein X is halogen and is selected from chlorine or bromine
with ethylene glycol compound of formula-3 in the presence alkoxide base like sodium tertiary butoxide or potassium tertiary butoxide in a suitable aprotic solvent which includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyl tetrahydrofuran, preferably tetrahydrofuran to provide bosentan compound of formula-1.
The second aspect of the present invention provides a process for the preparation of high pure bosentan, which comprises of the following steps;
a) Suspending the bosentan compound of formula-1 in a mixture of solvents selected from alcohols like methanol, ethanol, isopropanol, n-propanol, butanol and aqueous ester solvents like aqueous ethylacetate and aqueous isopropylacetate
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and dried to get the pure bosentan compound of formula-1.
The prior art process involves the recrystallisation of bosentan from a mixture of isopropyl acetate and methanol to remove the dimer impurity. However the purity of the obtained bosentan is not satisfactory after the first purification, four or five repeated crystallizations are required to attain a desire purity of bosentan according to ICH guidelines. The repeated crystallization leads to the increase in processing time and loss in the yield of the final product and hence increases the overall cost of production. In order reduce the number of purifications, we carried out number of recrystallisation of bosentan using a mixture of alcohol and ester solvents in different ratio with respect to the weight of the bosentan and surprisingly found that the usage of water along with mixture of alcohol and ester solvent leads to the maximum purity in single recrystallisation. The preferable ratio of alcohol and ester solvent is 1:1 with respect to the weight of the bosentan and having water content up to 5 to 25 % with respect to weight of the bosentan (for example: for 25 grams of bosentan a mixture of 25 ml of alcohol and 25 ml of ester solvent and 2 ml of water is used).

In a preferred embodiment, the purification of bosentan comprises of the following steps;
a) Suspending the bosentan compound of formula-1 in a mixture of methanol and ethylacetate in the ratio of 1:1 with respect to the bosentan and having water from 5 to 25% with respect to weight of bosentan,
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and drying to get the pure bosentan compound of formula-1.
The third aspect of the present invention relates to 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-6a. The said compound is an impurity which is formed during the preparation of bosentan, and it was isolated, characterized and prepared and having the following general structural formula-6a.

Isopropyl impurity of the present invention is characterized by 'H NMR (300 MHz) 5(ppm): 9.00-8.99 (d, .7=4.74 Hz, 2H), 8.72 (b, 1H), 8.45-8.43 (d, .7=8.22 Hz, 2H), 7.42-7.39 (m, 3H), 7.15-6.85 (m, 4H), 4.84 (s, 1H), 4.58 (s, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 2.92 (m, 1H), 1.22 (d, .7=6.81 Hz, 6H); Mass spectra m/z = 560 (M+Na)+.
The present invention also relates to an alkali metal salts of compound of formula-6 having the following structural formula.


Wherein M is an alkali metal ion.
Extensive research on this impurity formation revealed that the origin of the "Isopropyl impurity" is the presence of 4-isopropyl benzene sulfonamide as an impurity in 4-tertiary butyl benzene sulfonamide, the key raw material used in the preparation of bosentan. The 4-isopropyl benzene sulfonamide impurity present in the stating material reacts with 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4 and then subsequently reacts with ethylene glycol to provide 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-6a i.e. the isopropyl impurity.
The present invention also provides a process for the preparation of isopropyl impurity or its alkali metal salt compound of formula-6, which comprises of the following steps; a) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4
Formula-4 wherein X is a halogen; with 4-isopropyl benzene sulfonamide,


in presence of a base and a suitable solvent in the presence or absence of a phase transfer catalyst, to provide 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-5,

Formula-5 wherein X is a halogen and M is H or alkali metal ion, b) reacting 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-5, with ethylene glycol in the presence of a base in presence of a suitable solvent to provide 4-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzene sulfonamide (isopropyl impurity) or its alkali metal salt compound of formula-6.

Formula-6 wherein X is a halogen and M is hydrogen or an alkali metal ion.
In step a) the coupling of the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4 with 4-isopropyl benzene sulfonamide, 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 solvent includes but is not limited to

benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures thereof, preferably toluene.
The phase transfer catalyst is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl 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 step b) 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide is reacted with ethylene glycol in the presence of a base and a suitable aprotic solvent, with or without a phase transfer catalyst to obtain 4-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzene sulfonamide or its alkali metal salt compound of formula-6 (isopropyl impurity). 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; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride. The suitable solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyltetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, propanol, isopropanol and the like and their mixtures thereof.
The formation of isopropyl impurity is schematically represented by the following scheme:

As the said isopropyl impurity can not be removed by any of the conventional purification technique and hence its necessary to control in the origin itself other wise there is no other way to remove this impurity. Hence it necessary to develop a process to control rather than removing this isopropyl impurity, the present inventor developed an improved process to control this impurity well with in the limit as per ICH guidelines in the preparation of bosentan.
The fourth aspect of the present invention provides an improved process for the preparation of bosentan monohydrate compound of formula-1 substantially free of isopropyl impurity, which comprises of;
a) Condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of
formula-4,
Formula-4 Wherein X is halogen
with 4-tert-butylbenzene sulfonamide having less than 0.15%, preferably 0.10% of 4-
isopropylbenzene sulfonamide impurity, in presence of a suitable base in a suitable solvent
in presence or absence of a phase transfer catalyst to provide 4-tert-butyl-N-[6-halo-5-(2-
methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-2,
b) reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene
sulfonamide compound of formula-2

Formula-2 Wherein X is halogen,
with ethylene glycol compound of formula-3 in the presence a suitable base in a suitable solvent to provide bosentan compound of formula-1,

c) purifying the obtained bosentan compound of formula-1 using a suitable solvents selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol and ester solvents like ethyl acetate and isopropyl acetate and their mixtures or their aqueous mixtures to provide pure bosentan compound of formula-1.
In step a) the coupling of the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4 with 4-tert-butylbenzene sulfonamide, 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. The suitable solvent includes but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures thereof.
The phase transfer catalyst is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl 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 step b) 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide is reacted with ethylene glycol in the presence of a base and a suitable aprotic solvent, with or without a phase transfer catalyst to obtain bosentan compound of formula-1. 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; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride. The suitable solvent includes but is not limited to benzene, toluene, xylene,

acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, n-propanol, isopropanol and the like and their mixtures thereof.
The process for the preparation of bosentan monohydrate compound of formula-1 free of isopropyl impurity is represented by the following scheme.

The 1H NMR data of isopropyl impurity was recorded in CDCI3 solvent on BRUKER 300 MHz spectrometer using TMS as internal standard. The mass spectrum of isopropyl impurity was recorded on positive Ql MS by mass spectrometer.
The related substances of bosentan measured using HPLC with the following chromatographic conditions: Apparatus : A liquid chromatograph is equipped with variable wave length UV detector; Column : BDS hypersil C18, 250 X 4.6 mm, 5um or Equivalent; Flow rate : 0.8 ml/min.; Wave length: 220 nm.; Temperature : 30°C; Load: 20µl using aqueous methanol and aqueous methanolic dipotassium hydrogen orthophosphate in ratio of 1:1 as a diluent.

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as a limitation of the scope of the invention.
Examples:
Example-1: Preparation of bosentan compound of formula-1.
A mixture of ethylene glycol (formula-3) (300 grams), sodium tertiary butoxide (37.3 grams), and tetrahydrofuran (200 ml) was heated to 70-75°C and stirred for four hours. The reaction mixture was cooled to 25-30°C and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide (formula-2a) (50 grams) was added to it. The reaction mixture was heated to 70-75 °C and stirred for 12 hours. The reaction mixture was cooled to 25°C, quenched with water and then acidified with aqueous hydrochloric acid. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 45 grams
Purity by HPLC: 98.40%; 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ol (monochloro impurity): 0.11%; Pyrimidinone impurity: 0.22%; dimer impurity: 0.62%; formula-2a:0.13%; 0.53 RRT impurity: 0.20%
Reference Example-1: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and isopropyl acetate (25 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3 hours. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound Yield: 13 grams Purity by HPLC after three purifications: 99.72 %; dimer impurity: 0.07 % by HPLC
Reference Example-2: Purification of bosentan compound of formula-1:
Bosentan (44 grams) was dissolved in a mixture of methanol (44 ml) and ethyl acetate (44 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3 hours. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound Yield: 40 grams Purity by HPLC after 4 repeated purification: 99.73 %; dimer impurity: 0.05 % by HPLC

Example-2: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (25 ml) and water (2 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound Yield: 11 grams
Purity by HPLC after 2 purifications: 99.83 %; 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ol (monochloro impurity): Not Detected ; Pyrimidinone impurity: 0.04%; dimer impurity: 0.06%; formula-2a: Not Detected; 0.53 RRT impurity: Not detected
Example-3: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (25 ml) and water (4 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound Yield: 10 grams Purity by HPLC after 2 purifications: 99.85 %; dimer impurity: 0.02 % by HPLC
Example-4: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (20 ml) isopropylacetate (5 ml) and water (2 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound Yield: 10 grams Purity by HPLC after 2 purifications: 99.87 %; dimer impurity: 0.04 % by HPLC
Example-5: Preparation of 4-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy) (2,2'-bipyrimidin)-4-yl] benzene sulfonamide compound of formula-5a:
Potassium carbonate (3.5 grams) and tetra butyl ammonium bromide (1.0 grams) was added to a solution of 4-isopropyl benzene sulfonamide (4.8 grams) in toluene (60 ml) and then heated it into 50°C. A solution of 5-(2-methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro

pyrimidine (formula-4a) (6.0 grams) in toluene (120 ml) was slowly added to the reaction mixture and it was refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25 °C and acidified with aqueous hydrochloric acid. The reaction mixture was stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 8.7 grams
Example-6: Preparation of 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide (formula-6, isopropyl impurity):
A mixture of ethylene glycol (30.27 grams), sodium tertiary butoxide (3.75 grams), and tetrahydrofuran (20 ml) was heated to 70-75 °C and stirred for four hours. The reaction mixture was cooled to 50°C and 4-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide (5.0 grams) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred for 12 hours. The reaction mixture was cooled to 25°C, quenched with water and the reaction mixture acidified with aqueous hydrochloric acid. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 4.5 grams
Example-7: Preparation of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yI] benzene sulfonamide compound of formula-2a:
A mixture of 4-teriary butyl benzene sulfonamide (15.2 grams) having 0.11% of 4-isopropyl benzene sulfonamide, potassium carbonate (19.77 grams), tetrabutylammonium bromide (0.7 grams) in toluene (750 ml) was heated to 45-50°C and stirred for 30 minutes. 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (25 grams) was added the above mixture and heated to reflux temperature then stirred for 12 hours. The reaction mixture was cooled and then quenched with water. The reaction mixture was filtered and washed the solid with water. Acetonitrile (300 ml) was added to wet solid and heated to reflux temperature then stirred for 2 hours. Water (50 ml) was added the above wet solid and acidified with hydrochloric acid. The solid was filtered, washed with water and dried to get the title compound. Yield: 80 grams Purity by HPLC: 98.97 %; isopropyl derivative: 0.11%

Example-8: Preparation of bosentan monohydrate:
A mixture of ethylene glycol (formula-3) (301 grams), sodium tertiary butoxide (37.3 grams), and tetrahydrofuran (200 ml) was heated to 70-75°C and stirred for four hours. 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide (formula-2a) (50 grams) having less than 0.11 % of 4-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide was added to the reaction mixture and stirred for 12 hours at 70-75°C. The reaction mixture was cooled to 25°C, quenched with water and then acidified with aqueous hydrochloric acid. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 44 grams Purity by HPLC: 99.64 %; Isopropyl impurity: 0.10%
Examples 9 to 11:
Bosentan monohydrate compound of formula-1 is prepared analogues to the exmple-7 & 8, except that 4-tertiary butyl benzene sulfonamide with different levels of 4-isopropyl benzene sulfonamide impurity is used as input. The purity results of the experiments are tabulated in the following table, which shows the level of 4-isopropyl benzene sulfonamide in the starting 4-tertiary butyl benzene sulfonamide and corresponding isopropyl derivative formed in the final bosentan compound.

We Claim:
1. 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)
benzene sulfonamide or its salt compound represented by the following general structural
formula
Wherein M is hydrogen or alkali metal ion.
2. 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)
benzene sulfonamide compound represented by the following structural formula

characterized by at least one of lH NMR (300 MHz) 8(ppm): 9-8.99 (d, .7=4.74 Hz, 2H), 8.72 (b, 1H), 8.45-4.43 (d, .7=8.22 Hz, 2H), 7.42-7.39 (m, 3H), 7.15-6.85 (m, 4H), 4.84 (s, 1H), 4.58 (s, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 2.92 (m, 1H), 1.22 (d, .7=6.81 Hz, 6H) & Mass spectra m/z=560 (M+Na)+.
3. A process for the preparation of 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide or its salt compound of
formula-6, which comprises of the following steps;
a) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4


Formula-4 wherein X is a halogen; with 4-isopropyl benzene sulfonamide,

in presence of a base and a suitable solvent in the presence or absence of a phase transfer catalyst, to provide 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-5,

Formula-5 wherein X is a halogen and M is an alkali metal ion, b) reacting 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-5, with ethylene glycol in the presence of a base in presence of a suitable solvent to provide 4-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl] benzene sulfonamide (isopropyl impurity) or its alkali metal salt compound of formula-6.
4. An improved process for the preparation of bosentan monohydrate compound of formula-1 substantially free of isopropyl impurity,


which comprise of the following steps;
a) Condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine
compound of formula-4,
Wherein X is halogen
with 4-tert-butylbenzene sulfonamide having less than 0.15% of 4-isopropylbenzene sulfonamide impurity, in presence of a suitable base in a suitable solvent in presence or absence of a phase transfer catalyst to proivde p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-2,
b) reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]
benzene sulfonamide compound of formula-2

Wherein X is halogen,
with ethylene glycol compound of formula-3 in the presence a suitable base in a
suitable solvent to provide bosentan compound of formula-1,
c) purifying the obtained bosentan compound of formula-1 using a suitable solvents to
provide pure bosentan compound of formula-1.

5. The process according to claim 3 & 4) characterized by any one of the following;
In step a) wherein the suitable base used is selected from the group consisting of 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; and the suitable solvent selected from benzene, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran and their mixtures thereof; and a 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 triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
In step b) wherein the base used is selected from base is selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; and the suitable solvent used is selected from benzene, toluene, xylene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, propanol, isopropanol and the like and their mixtures thereof.
6. A process for the preparation of highly pure bosentan comprise of the following steps;
a) Suspending the bosentan compound of formula-1 in a mixture of solvents selected from alcohols like methanol, ethanol, isopropanol, n-propanol, butanol and ester solvents like ethylacetate, isopropylacetate and water or mixtures thereof,

b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and dried to get the pure bosentan compound of formula-1.
7. A process for the preparation of highly pure bosentan comprise of the following steps;
a) Suspending the bosentan compound of formula-1 in a mixture of water, methanol and ethylacetate,
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with cyclohexane and dried to get the pure bosentan compound of formula-1.

8. A process according to claim 6, wherein in step a) the alcohol or ester solvent is used in an amount of about 1 ml to about 2 ml per 1 gram of bosentan and water is used in an amount about 5 to about 25% with respect to the weight of bosentan.
9. An improved process for the preparation of bosentan monohydrate compound of formula-1,

which comprises reacting the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-2a


Formula-2a with ethylene glycol compound of formula-3 in the presence alkoxide base like sodium tertiary butoxide or potassium tertiary butoxide in a suitable aprotic solvent like benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyl tetrahydrofuran, to provide bosentan compound of formula-1.
10. Bosentan compound of formula-1, having the impurity 4-Isopropyl-N-(6-(2-hydroxy ethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-6a (isopropyl impurity) in a concentration less than 0.15%, preferably 0.10%, more preferably 0.05%.

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