1. An improved process to synthesize dual endothelin receptor antagonist bosentan, said process comprises: (a) reacting diethylbromomalonate (III) and 2-methoxy phenol (IV) to obtain diethyl 2-(2-methoxyphenoxy) malonate (V), (b) reacting diethyl 2-(2-methoxyphenoxy) malonate (V) with pyrimidine-2-carboximidamide salt (VII) in the presence of alkali metal alkoxide and a solvent to obtain 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII), (c) reacting 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII) with a dehydrating agent to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX), (d) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX) with 4-(tert-butyl) benzene sulfonamide (XI) in the presence of a suitable alkali carbonate and a solvent at specific reaction conditions to obtain 4-(tert- butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII), (e) reacting 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'- bipyrimidin]-4-yl) benzene sulphonamide (XII) with ethylene glycol at a specific temperature ranging from 75 °C to 85 °C, in the presence of a suitable base, alkali metal alkoxide and a transition metal catalyst to obtain crude form of highly pure bosentan, [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulfonamide (I).

2. The process as claimed in claim 1, wherein the alkali carbonate of step is selected from potassium carbonate, sodium carbonate, cesium carbonate and lithium carbonate or any combination thereof.

3. The process as claimed in claim 1, wherein the solvent is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, n-butanol, dioxane or any combination thereof.

4. The process as claimed in claim 1, wherein the alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, or any combination thereof.

5. The process as claimed in claim 1 wherein said base is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, acetonitrile, n-butanol, dioxane or any combination thereof.

6. The process as claimed in claim 1 wherein said dehydrating agent is selected from phosphoryl chloride (POCh), phosphoric anhydride (P2O5), 1,3,5-trichlorotriazine.

7. The process as claimed in claim 1 wherein said specific reaction conditions in step (d) are temperature ranging from 80 °C to 120 °C and reaction time between 10 hours to 14 hours.

8. The process as claimed in claim 1 wherein said temperature in step (e) is 80 °C.

9. The process as claimed in claim 2 wherein said alkali carbonates are potassium carbonate or cesium carbonate or a mixture thereof.

10. The process as claimed in 3 wherein said solvent is acetone.

11. The process as claimed in claim 4, wherein said alkali metal alkoxide is lithium t-butoxide.

12. The process as claimed in claim 6, wherein said dehydrating agent is phosphoryl chloride.

13. The process as claimed in claim 7, wherein said specific reaction conditions are temperature of 100 °C for 12 hours.

14. The process as claimed in claim 1, wherein the transition metal catalyst in step (e) is copper iodide.

15. The process as claimed in claim 1, wherein yield of said crude bosentan is 93.35% or more.

16. The process as claimed in claim 1, wherein purity of said crude bosentan is 92.87% or more.

17. The process as claimed in claim 1, wherein said crude bosentan is crystallized to obtain pure bosentan using a polar aprotic solvent, a polar protic solvent or their mixtures.

18. The process as claimed in claim 17, wherein said polar aprotic solvents are selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate tetrahydrofuran or any combination thereof.

19. The process as claimed in claim 18, wherein said polar aprotic solvent is ethyl acetate.

20. The process as claimed in claim 17, wherein the polar protic solvents are selected from water, ethanol, methanol, ammonia, acetic acid, or any combination thereof.

21. The process as claimed in claim 20, wherein the polar protic solvent is methanol.

22. The process as claimed in claim 17, wherein the pure Bosentan is more than 99.9% pure.

23. The process as claimed in claim 16, wherein the pure Bosentan is 100% pure.

24. The process as claimed in claim 16 wherein yield of pure bosentan is 81.05 % or more.

25. The process as claimed in claim 1, wherein the Bosentan obtained is free from bis sulfonamide impurity.

26. A pharmaceutical composition comprising Bosentan capable of being used in endothelin-receptor mediated disorders.

FIELD OF THE INVENTION
The present invention relates to an improved process to synthesize dual endothehn receptor antagonist Bosentan, chemically known as [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulfonamide. More specifically, the present invention relates to an exceedingly facile and cost-effective process for coupling of p-tert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]4yl]benzenesulfonamide and ethylene glycol in the presence of a catalyst Cul and mild base lithium tert-butoxide to obtain Bosentan with high purity and enhanced yield. The invention also relates to the intermediates formed during the process. The invention further relates to the highly pure bosentan obtained by the process.
BACKGROUND OF THE INVENTION
Bosentan monohydrate sold under the brand name Tracleer, is an orally active antihypertensive drug indicated in the treatment of pulmonary arterial hypertension (PAH), first approved by the FDA in November 2001. Bosentan inhibits the action of endogenous vasoconstrictor and bronchoconstrictor endothehn 1 by blocking endothehn A and endothehn B receptors available in the endothelium and vascular smooth muscle. Bosentan decreases both pulmonary and systemic vascular resistance and is particularly used in the treatment of pulmonary arterial hypertension. It has a high protein binding rate (98%), especially to albumin.
i °"

f Y N NH
^N 0=S=0
Bosentan

Various synthetic procedures of Bosentan have been reported in scientific literatures in the past few years.
Bosentan and its analogs were first reported as endothelin (ET) receptor antagonist in US patent no. 5292740) in the year 1994 This compound included reaction of pyrimidine-2-carboximidamide hydrochloride and dimethyl 2-(2-methoxyphenoxy) malonate using sodium methoxide as base to obtain 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol, which on chlorination yielded dichloropyrimidine intermediate (4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine. One of the chlorines of dichloro intermediate was replaced with 4-tert butyl benzene sulphonamide to yield 4-(tert-butyl)-N-(6-chloro-5-(2-methoxy phenoxy)-[2,2'-bipyrimidin]-4-yl) benzenesulfonamide. The reaction of this intermediate with sodium ethylene glycolate (Na metal and Ethylene glycol) yielded sodium salt of bosentan with overall yield of 53%. The process involved use of mono sodium ethylene glycol prepared by treating ethylene glycol in sodium metal. It has been found difficult to execute this step at industry level. Another major disadvantage is formation of bis-sulphonamide dimer impurity removal of which requires tedious work up procedures which in turn increases cost of preparation. Furthermore, this multi-step synthetis requires use of mixtures of solvents, making the entire synthesis costly to be executed at industrial scale.

1

O O'

1
N J-* J^ f Y^N NH

II

The second synthetic route with improved features was reported in US patent no. 6 136971 to avoid use of excess ethylene glycol by the use of protected ethylene glycol. Disadvantages of this method includes multi step synthesis, use of expensive ethylene glycolate mono tert-butyl ether, large volume of solvents, as well as tedious processes of protection and deprotection which further increases cost of synthesis, excess exposure of manpower to the solvents leading a difficult task for industries.
WO 2010032261 Al provides improved processes for preparing Bosentan and novel intermediates like 4,6-dihydroxy-5-(2-methoxy phenoxy)[2,2'] bipyrimidine of formula (II) and N-(6-Chloro-5-(2- ethoxyphenoxy)[2,2'-bipyrimidinyl]-4-t-butyl benzenesulfonamide cesium salt and process for preparation thereof. The invention also disclosed novel polymorphic form of the intermediates.
US8664390B2 relates to an improved process for the preparation of Bosentan. In particular it relates to a process for preparing Bosentan substantially free from the dimer impurity of formula (II) and the 6-hydroxy impurity of formula (III). The invention also relates to a pharmaceutical composition comprising Bosentan and its use in the treatment of endothelin-receptor mediated disorders.
US8785461B2 relates to a novel intermediate useful in the preparation of Bosentan and to processes for the preparation of said intermediate and Bosentan. The invention further relates to compositions comprising Bosentan prepared according to the processes of the invention and their use in the treatment of endothelin-receptor mediated disorders.
It is noteworthy that the synthetic procedures of obtaining Bosentan in the existing state of the art are associated with certain drawbacks such as use of toxic solvents and reagents, multistep synthesis and formation of potential impurities with low yield. In

nutshell, purification processes in existing protocols to achieve pure Bosentan are tedious, time consuming and requires large volumes of solvent.
Therefore, there is a need for developing a new process for the synthesis of bosentan that involve reduced number of reaction steps, lesser number of solvent(s) with no/less generation of impurities. The process should provide pure compound (bosentan) in high yields, and pure that can be performed at industrial level.
In order to obviate the drawbacks in the existing state of the art, the present invention provides an eco-friendly, cost effective and scale up synthetic procedure to achieve pure Bosentan with high yield. This invention also reports some novel information pertaining to electronic properties (HOMO-LUMO ) of bosentan employing DFT and FMO studies.
OBJECTS OF THE INVENTION
The main object of the present invention to provide an improved process to synthesize dual endothelin receptor antagonist Bosentan in highly pure form.
Another object of the present invention is to provide an exceedingly facile and cost-effective process to obtain Bosentan employing improved alternate synthesis with high purity and enhanced yield.
Yet another object of the present invention is to provide an improved process to
synthesize dual endothelin receptor antagonist Bosentan involving a modified UGI
coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-
bipyrimidin]4yl]benzenesulfonamide and ethylene glycol in the presence of a catalyst Cul and mild base lithium tert-butoxide.

Yet another object of the invention is to obtain substantially pure Bosentan suitable for pharmaceutical use.
SUMMARY OF THE INVENTION
It will nevertheless be understood that no limitation of the scope of the invention is thereby intended by way of embodiments and examples. Such alterations and further modifications in the present invention, and such further applications of the principles of the invention as would normally occur to those skilled in the art are to be construed as being within the scope of the present invention.
It will be understood by those skilled in the art that the summary of the invention provided herein is exemplary and explanatory of the invention and are not intended to be restrictive thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The composition, process, methods, and examples provided herein are only illustrative and not intended to be limiting.
The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more steps of method or components preceded by "comprises... a" does not, without more constraints, preclude the existence of other, steps or components. Appearances of the phrase "in a preferred embodiment", "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.
Accordingly, one of the aspects of the present invention is to provide an improved process to synthesize dual endothelin receptor antagonist Bosentan. The process of

the present invention is exceedingly facile and cost-effective process to obtain Bosentan employing improved alternate synthesis with high purity and enhanced yield.
The process comprises coupling of p-tert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin] 4yl]benzenesulfonamide and ethylene glycol (0.25 ml) as a two key starting materials catalyzed by the Cul and mild base lithium tert-butoxide. The process provides highly pure Bosentan with more than 80% yield.
The steps of the process are depicted in Scheme 1,2,3. In this invention, the ethylene glycol is used as both reactant as well as solvent. The 0.25 ml of ethylene glycol is used with respect to sulfonamide.
The process provides intermediates formed during the process to synthesize dual endothelin receptor antagonist Bosentan. The process is a cost-effective and time-effective process to synthesize Bosentan with high yield and high purity.
The process provides the Bosentan without formation of any unwanted by-product, as confirmed from crude LCMS analysis. Thus, the critical purification step is completely eliminated in the present protocol. The process is cost effective and commercially suitable as it involves the milder reaction conditions.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 shows the optimized structure of Bosentan [Colour Code: C-Dark grey, H-
Light grey, N-Dark blue, S-Yellow, O-Red].
Figure 2 shows the 3D Pictorial illustration of HOMO-LUMO showing energy gap of
Bosentan.
Figure 3 (a) shows the Isosurface plot of Bosentan.
Figure 3 (b) shows the MEP plot of Bosentan.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for synthesis of bosentan. The process is eco-friendly and yields highly pure bosentan without any additional purification steps. Also the bosentan obtained by the process is substantially free from impurities.
In one embodiment, the present invention provides a process for the synthesis of bosentan starting from Diethyl-2-bromomalonate (III) as represented by Scheme -1.
The process for synthesis of bosentan comprises:
(a) reacting diethylbromomalonate (III) and 2-methoxy phenol (IV) to obtain diethyl 2-(2-methoxyphenoxy) malonate (V),
(b) reacting diethyl 2-(2-methoxyphenoxy) malonate (V) with pyrimidine-2-carboximidamide salt (VII) in the presence of alkali metal alkoxide and a solvent to obtain 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII),
(c) reacting 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII) with a dehydrating agent to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX),
(d) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX) with 4-(tert-butyl) benzene sulfonamide (XI) in the presence of a suitable alkali carbonate and a solvent at specific reaction conditions to obtain 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII), said specific reaction conditions are a temperature ranging from 80 °C to 120 °C and reaction time of 10 hours to 14 hours.
(e) reacting 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII) with ethylene glycol at a temperature range of 75 °C 85 °C, in the presence of a suitable base, alkali metal alkoxide and a transition metal catalyst to obtain crude form of highly pure bosentan, [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulfonamide (I).

The suitable alkali carbonate is selected from potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate or any combination thereof. In a preferred embodiment the alkali carbonates are potassium carbonate or cesium carbonator a mixture thereof.
The suitable solvent is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, n-butanol, dioxane or any combination thereof. In a preferred embodiment the solvent is acetone.
The suitable alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide or any combination thereof. In a preferred embodiment the alkali metal alkoxide is lithium t-butoxide.
The base is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, acetonitrile, n-butanol, dioxane or any combination thereof.
The suitable dehydrating agent is selected from phosphoryl chloride (POCb), phosphoric anhydride (P2O5), 1,3,5-trichlorotriazine. In a preferred embodiment, the dehydrating agent is phosphoryl chloride.
The process yields 93.35 % or more of crude bosentan with 92.87% or more purity. The crude bosentan is crystalized to obtain highly pure bosentan with more than 99.9% purity without any detectable impurity. The yield of pure bosentan is 81.05 % or more.
In a preferred embodiment the present invention provides a process for the synthesis of Bosentan, comprising:

(a) reacting diethylbromomalonate (III) and 2-methoxy phenol (IV) to obtain diethyl 2-(2-methoxyphenoxy) malonate (V),
(b) reacting diethyl 2-(2-methoxyphenoxy) malonate (V) with pyrimidine-2-carboximidamide salt (VII) in the presence of sodium methoxide and solvent to obtain 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII),
(c) reacting 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII) with phosphoryl chloride and to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX),
(d) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX) with 4-(tert-butyl) benzene sulfonamide (XI) at a temperature of 100 °C for 12 hours in the presence of cesium carbonate and dimethylformamide to obtain 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII),
(e) reacting 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII) with ethylene glycol, in the presence of lithium t-butoxide, and copper iodide at 80 °C to obtain highly pure crude form of Bosentan, [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulfonamide (I).
The crude bosentan as prepared by the process as disclosed herein can be crystallized using a polar aprotic solvent, a polar protic solvent or their mixtures to obtain pure Bosentan with 100% purity.
The polar aprotic solvents are selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate tetrahydrofuran. In a preferred embodiment, the polar aprotic solvent is ethyl acetate.
The polar protic solvents are selected from water, ethanol, methanol, ammonia, acetic acid. In a preferred embodiment, the polar protic solvent is methanol.

In one embodiment, the present invention provides substantially pure Bosentan. As used herein, "substantially pure Bosentan" or "highly pure bosentan" refers to Bosentan wherein the total impurities is less than about 0.1% w/w as measured by high performance liquid chromatography ("HPLC"). In particular, the present invention provides substantially pure Bosentan wherein the said Bosentan is free from bis sulfonamide impurity.

In another one embodiment the present invention provides highly pure Bosentan with
more than 99.9% purity. In a preferred embodiment, the purity of bosentan is 100%).
K2C03 Acetone EtO
HO ^O
o o
vOEt
60 °C, 2h
O O
Etcr y ^oEt
Br
IV

NH
I N
VII
N 1)NaOCH3, MeOH, NL ^ 0°C to 20°C, 16 h ^N
N 2) NH4CI,
0°C to RT, 24 h
VI

OH O
NaOCH3, ? |T
N OH
VIM
MLJ ., ~, 80°C, 4-5h /N.J^./k,
NH2H-CI - »-r^ y

POCI3 ^ ^N-

CI
IX

Scheme-1



o=s=o

Ammonia,MDC, 0°C to RT 24h

NH2
o=s=o
XI

IX

CS2C03, DMF, 100°C, 12 h

Scheme-2

XII


Bosentan
I
Scheme-3
The synthetic process of the present invention yields 93.35 % crude besentan of 92.87% or more purity.
In an embodiment of the present invention, the pure Bosentan obtained by the process shows 100%) purity and 81.05 % or more yield having melting point in the range of 122°C. In an embodiment, the present invention also provides pharmaceutical composition comprising substantially pure Bosentan.
The pharmaceutical compositions of the present invention are prepared using conventional materials and techniques, such as mixing, blending and the like.
Examples:
Example 1: Synthesis of diethyl 2-(2-methoxyphenoxy) malonate from diethyl-2-
bromomalonate and 2-methoxy-phenol.
In a round bottom flask 2-methoxy phenol (20.56 g, 165.65mmol), K2CO3 (50.87 g,
368.10mmol) and dry acetone (150 mL) were heated at 60 °C for 2h. Then cool down
the reaction mixture to 0 °C and diethyl 2-bromomalonate (44.0 g, 184.05mmol) in

acetone (50 mL) was added drop wise with maintaining the reaction temperature
between 0 °C to 5 °C. Then reaction mixture was allowed to stir for 4-5 hrs at room
temperature. After completion of SM on TLC, the reaction mixture was diluted with
water (200 mL) and extracted with EtOAc (2x 100 mL), combined all organic layers,
dried over Na2S04, solvent was removed in vacuo to give 57.0 g of crude product
diethyl 2-(2-methoxyphenoxy) malonate which was purified from column
chromatography (silica gel 100-200, 0-15% ethyl acetate in hexane) to give pure
diethyl 2-(2-methoxyphenoxy) malonate (47.5 g, 91.42%).
TLC: (2.0:8.0, Ethyl acetate/Hexane, RF: 0.6).
Mass (ESI +ve): 283.1 [M+1H].
LCMS: 95.62% (LCMS-06, method-C3 (Mobile phase: 2mM Ammonium acetate,
0.1% FA in water: Acetonitrile), RT: 1.675 min).
1H NMR (400 MHz, Chloroform-d): 5 1.35 (t, J = 7.1 Hz, 6H), 3.90 (s, 3H), 4.35
(qq, J = 7.3, 3.6 Hz, 4H), 5.26 (s, 1H), 6.93 (dd, J = 15.3, 8.0, 1.5 Hz, 2H), 7.13 -
7.05 (m, 2H).
Example 2: Synthesis of pyrimidine-2-carboximidamide hydrochloride In a round bottom flask dry methanol (50 mL) was taken and Na Metal (1.31 g, 57.9 mmol) was added under nitrogen atmosphere to it with in 10 min of time then pyrimidine-2-carbonitrile (5 gm, 47.57mmol) was added to the reaction mixture and resulting reaction mixture was stirred for 24 hrs of time at room temperature. Then ammonium chloride (5.09 gm, 95.15mmol) was added to the reaction mixture and reaction mixture was stirred for 24 hrs of time at room temperature. The resulting reaction mixture was filtrated and filtrate was concentrated under high vacuum to afford crude pyrimidine-2-carboximidamide hydrochloride, washed it with hexane (2x10 mL) to give pyrimidine-2-carboximidamide hydrochloride (5.7 g, 75.55%) TLC: (1.0:9.0, MeOH/MDC, RF: 0.1). Mass (ESI+ve): 123.13 [M+1H].

LCMS: 92.5% (LCMS-08, method-G (Mobile phase: 20mM Ammonium acetate in Water: MeOH), RT: 3.61 min)
1H NMR (400 MHz, DMSO-d6): 5 7.89 (t, J = 4.9 Hz, 1H), 8.42 (bs, 4H), 9.12 (d, J = 4.9 Hz, 2H).
Example 3: Synthesis of 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol:
In a dry (500 mL) round bottom flask dry methanol (100 mL) was taken and Na metal (5.80 g, 252.2 mmol) was added to it in small portions under nitrogen atmosphere till it dissolved. Diethyl 2-(2-methoxyphenoxy) malonate (23.14 g, 63.03 mmol) was added to the above freshly prepared sodium methoxide and resulting reaction mixture was stirred at room temperature for 30 min. To this mixture, pyrimidine-2-carboximidamide hydrochloride (10 g, 63.03 mmol) was added and stirred at 80 °C for 5-6 h. After completion of the reaction, the reaction mixture was cooled to 25-30 °C and then poured on to the ice. The pH of the reaction mixture was adjusted to 2-3 by adding dilute HC1. The solid obtained was filtered and, washed with water (15 mL). The product was dried under vacuum to give 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol as a white solid (5 g, 25.39 % yield), m.p.: 276-277 °C Mass (ESI-MS): 313.33 [M+l], 335.33 [M+23]. LCMS: 100%
*H NMR (400 MHz, DMSO-d6): 5 3.83 (s, 3H), 6.67 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.7 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 4.9 Hz, 1H), 9.05 (d, J = 4.9 Hz, 2H), 12.24 (s, 1H, D20 exchangeable), 12.58 (s, 1H, D20 exchangeable).
13C NMR (100 MHz, DMSO-d6): 5 56.04, 113.13, 113.54, 120.85, 121.52, 122.27, 123.34, 146.80, 148.75, 149.70, 157.22, 158.51, 168.80
Example 4: Synthesis of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine [IX]

5-(2-Methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol [VIII] (12.5 g, 40.03 mmol) was taken in a sealed tube and 90 ml (960 mmol) of phosphoryl oxy chloride was added to it. The reaction mixture was heated at 100 °C for 4-5 h. The reaction mixture was cooled at room temperature and -quenched with ice cold water (150 mL) and was extracted with dichloromethane (3x100 mL), The combined organic layer was washed with brine solution (10%), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the crude 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine [4], which was purified by column chromatography (on silica gel: 100-200 mesh) using 0-2% MeOH in dichloromethane as eluent to furnish pure 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine [4] as a brown solid. Yield: 5.09 g, 36.42 %. m.p. 138-140 °C Mass (ESI-MS): 349.6 [M], 351.6 [M+2H]. LCMS: 97.96%
1H NMR (400 MHz, DMSO-d6): 5 3.87 (s, 3H), 6.89 (td, J = 7.7, 1.6 Hz, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 7.24 -7.09 (m, 2H), 7.74 (t, J = 4.8 Hz, 1H), 9.09 (d, J = 4.9 Hz, 2H).
Example 5: Synthesis of 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide [XII]
In a 100 mL dry round bottom flask, 4-(tert-butyl) benzene sulfonamide [XI] (3.97 g, 18.62 mmol) was taken and cesium carbonate (9.33 g/28.64 mmol) and DMF (10 mL) were added to it. The resulting reaction mixture was stirred at room temperature for 20-30 min. To this 4, 6-dichloro-5-(2-methoxyphenoxy)-2, 2'-bipyrimidine [IX] (5 g, 14.32 mmol) was added and the mixture was stirred at 100-105 °C for 12 hrs. After completion of the reaction (through TLC), the mixture was cooled to room temperature and acidified with dilute HC1 to adjust the pH of the mixture to 2-3. Reaction mass was extracted with ethyl acetate (3x 50 mL) and dried over anhydrous sodium sulphate to give crude 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-

[2,2'-bipyrimidin]-4-yl) benzenesulfonamide [XII], which was further purified from column chromatography (on silica gel: 100-200 mesh), using 0-3 % methanol in dichloromethane as eluent to afford pure 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) benzenesulfonamide as a light brown solid. Yield: 5 g, 66.38% yield, m.p.: 214-216 °C. Mass (ES-MS ): 526.39 [M], 528.37 [M+2H]. LCMS: 96.17%
1H NMR (400 MHz, DMSO-d6): 5 1.27 (s, 9H), 3.73 (s, 3H), 6.77 (d, J = 7.9 Hz, 1H), 2H), 6.85 (s, 1H), 7.11 (t, J = 9.5 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 4.7 Hz, 1H), 8.29 (s, 2H), 9.14 (d, J = 4.8 Hz, 2H), 12.13 (bs, 1H).
Example 6: Synthesis of Bosentan
In a 250 mL round bottom flask ethylene glycol [XIII] (53.0 mL) was taken and lithium tert-butoxide (1M solution in THF) (7.61 g, 95.06 mL, 95.06 mmol) was added to it slowly drop by drop. To this 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) benzenesulfonamide [XII] (5 g, 9.51 mmol) was added and the mixture was stirred for 5-10 min. Subsequently, Cul (190.45mg, 0.951 mmol) was added to it. The mixture was stirred at 80 °C for 7-8 h. It was cooled to room temperature and its pH was adjusted to 3-4 by adding dilute HCl. The mixture was extracted with dichloromethane (3x50 mL), and was washed with brine solution (10%), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude bosentan with 95.35 % yield.
Example 7: Purification of Bosentan
The crude bosentan was dissolved in a mixture of methanol and ethyl acetate (1:1). To this solution activated charcoal was added. The mixture was heated at 70°C for 1-2 h. It was cooled to room temperature and passed through a celite column, washed with a hot mixture of MeOH and ethyl acetate (1:1). The filtrate was concentrated and residue on further crystallization, from a mixture MeOH and ethyl acetate gave white

crystals of Bosentan with 100% purity, 4.25 g (81.05 %) yield having melting point in the range of 122°C.
Example 8: Computational Studies
Theoretical studies for bosentan were carried out using Gaussian'09 software suite. The drug structure has been built and optimized structure was visualized with the sofftware Gauss View version 5.0.9. The optimization of the structure of compounds were carried out using DFT method in gaseous phase. Structure of the bosentan has been fully optimized at the B3LYP /6-311++g(d, p) level. Optimized structure for the bosentan is depicted in the Figure 1 with atomic numbering.
Different molecular parameters like dipole moment, single point energy (E), atomic distances and angles were summarized. Atomic distances and angles obtained from the optimized structure were compared with the X-ray crystal study reported earlier. Theoretical results are in good agreement with experimental results. Table 2 and Table 3 listed the comparative atomic distances and angles of the targeted compound. First Excitation energy which is also called HOMO-LUMO energy gap (AE) is calculated 0.1557 eV, suggested the possibility of charge transfer with in the molecule (Figure 2). Other important global reactivity descriptors namely chemical potentials (u), ionization potential (I), electronegativity (X), electron affinity (E), chemical hardness (n), chemical softness (S), global softness (o) electrophilicity index (co), and ANmaxwere calculated. The values of all the reactivity descriptors are reported in Table 4. In order to understand the charge loci of the drug molecule bosentan electrostatic potential (ESP) study has also been carried out.
The optimization of the structure of compounds were carried out using DFT method in gaseous phase. Structure of the bosentan has been fully optimized at the B3LYP/6-311++g(d, p) level.

Bond Length and bond angles obtained from the optimized structure were compared with the X-ray crystal study reported earlier. The results obtained theoretically are in good agreement with experimental data. Table 1 and Table 2 listed the bond lengths and bond angles of the targeted compound along with their comparison with experimental results. The frontier molecular orbital (FMOs) theory assisted to understand the mode in which the molecules interact with each other. EHOMO (energy of highest occupied molecular orbital) and ELUMO (lowest unoccupied molecular orbital), refers to eigen value of the highest occupied orbitals and lowest unoccupied orbitals respectively. HOMO orbitals have electron donating propensity whereas LUMO orbitals have tendency to accept electrons. The ionization potential and electron affinity are the negative of the orbital energy of HOMO and LUMO respectively. Energy gap also known as HOMO-LUMO gap, the lowest energy electronic excitation possible in a compound is always positive. The HOMO and LUMO were investigated for tri and tetra nuclear compounds (Table 3). The energy gap was found to be 0.165 eV for synthesized compounds (Figure 2). Energy gap value suggest the possibility of charge transfer. The hardness of a molecule is due to the large HOMO-LUMO Energy gap. The values of all the reactivity descriptors are reported in Table 3.
Table 1 Optimized bond length (A) of of Bosentan

Parameters Bond length Parameters Bond length

Exp Theoretical
Exp Theoretical
C1-C2 1.383 1.3908 C15-H19 0.9500 1.0837
C1-C4 1.378 1.3908 C16-C18 1.376 1.3921
Ci-Hs 0.9500 1.0826 C16-H20 0.9500 1.0836
C2-H6 0.9500 1.0867 C18-H21 0.9500 1.0833
C2-N24 1.337 1.3328 N27-S42 1.6455 1.7172

C3-C8 1.501 1.5021 N27-H55 0.8800 1.0133
C3-N23 1.339 1.338 C28-H29 0.9800 1.0893
C3-N24 1.329 1.3395 C28-H30 0.9800 1.0952
C4-H7 0.9500 1.0867 C28-H31 0.9800 1.0917
C4-N23 1.338 1.3327 C28-O32 1.427 1.4348
C8-N25 1.333 1.3286 C33-C34 1.499 1.5192
C8-N26 1.333 1.3359 C33-H35 0.9900 1.0899
C9-C11 1.392 1.3998 C33-H36 0.9900 1.0899
C9-N26 1.331 1.3263 C33-O39 1.450 1.4528
C9-O39 1.338 1.3418 C34-H37 0.9900 1.0932
C10-C11 1.400 1.3993 C34-H38 0.9900 1.0968
C10-N25 1.338 1.3358 C34-O40 1.425 1.4208
C10-N27 1.376 1.3808 O40-H41 0.8400 0.9649
C11-O22 1.372 1.3746 S42-O43 1.4324 1.4526
C12-C13 1.398 1.4034 S42-O44 1.4365 1.4605
C12-C14 1.373 1.3914 S42-C45 1.757 1.7911
C12-O22 1.400 1.3904 C45-C46 1.386 1.3903
C13-C15 1.396 1.3931 C45-C47 1.386 1.3943
C13-O32 1.369 1.3703 C46-C48 1.392 1.3939
C14-C16 1.401 1.3955 C46-H49 0.9500 1.0825
C14-H17 0.9500 1.0836 C47-C50 1.381 1.3891
C15-C18 1.387 1.3936 C47-H51 0.9500 1.0828
C48-C52 1.395 1.3998 C48-H53 0.9500 1.0815

C50-C52 1.391 1.405 C50-H54 0.9500 1.0835
C52-C56 1.536 1.5381 C56-C57 1.520 1.5471
C56-C61 1.520 1.5394 C56-C65 1.537 1.5468
C57-H58 0.9800 1.0924 C57-H59 0.9800 1.0942
C57-H60 0.9800 1.0934 C61-H62 0.9800 1.0932
C61-H63 0.9800 1.0935 C61-H64 0.9800 1.0933
C65-H66 0.9800 1.0921 C65-H67 0.9800 1.0935
C65-H68 0.9800 1.0943
Table 2 Optimized bond angles (°) of of Bosentan

Parameters Bond angle Parameters Bond angle Parameters Bond angle

Exp Theoretical
Exp Theoretical
Exp Theoretical
C2-C1-C4 116.55 116.152 N25-C10-N27 118.65 119.303 C34-C33-H36 109.8 110.559
C2-Ci-H5 121.7 121.898 C9-C11-C10 116.46 116.340 C34-C33-O39 109.51 110.437
C4-Ci-H5 121.7 121.950 C9-C11-O22 123.34 123.803 H35-C33-H36 108.2 110.749
C1-C2-H6 118.8 121.118 C10-C11-O22 119.96 119.624 H35-C33-O39 109.8 109.761
C1-C2-N24 122.32 122.436 C13-C12-C14 120.89 120.529 H36-C33-O39 109.8 104.0752
H6-C2-N24 118.8 116.446 C13-C12-O22 115.26 116.305 C33-C34-H37 109.4 108.375
C8-C3-N23 116.71 116.960 C14-C12-O22 123.86 123.101 C33-C34-H38 109.4 109.830
C8-C3-N24 116.86 117.236 C12-C13-C15 118.85 118.879 C33-C34-O40 111.16 112.941
N23-C3-N24 126.42 125.800 C12-C13-O32 116.62 121.625 H37-C34-H38 108.0 107.652

C1-C4-H7 118.8 121.223 C15-C13-O32 124.53 119.388 H37-C34-O40 109.4 106.327
C1-C4-N23 122.46 122.386 C12-C14-C16 119.65 119.864 H38-C34-O40 109.4 111.475
H7-C4-N23 118.8 116.391 C12-C14-H17 120.2 119.730 C9-O39-C33 118.20 119.041
C3-C8-N25 115.81 116.937 C16-C14-H17 120.2 120.386 C34-O40-H41 109.5 108.700
C3-C8-N26 116.56 116.898 C13-C15-C18 120.29 120.894 N27-S42-O43 110.81 109.093
N25-C8-N26 127.63 126.164 C13-C15-H19 119.9 117.824 N27-S42-O44 102.75 101.740
C11-C9-N26 122.68 121.8682 C18-C15-H19 119.9 121.282 N27-S42-C45 106.09 105.016
C11-C9-O39 115.93 117.1739 C14-C16-C18 120.1 120.104 O43-S42-O44 119.06 121.578
N26-C9-O39 121.38 120.9572 C14-C16-H20 120.0 119.426 O43-S42-C45 109.13 109.626
Cll-Cl0-N25 121.54 121.602 C18-C16-H20 120.0 120.464 O44-S42-C45 108.18 108.396
Cll-Cl0-N27 119.81 119.080 S42-C45-C46 121.29 118.400 H66-C65-H68 109.5 107.768
Cl5-Cl8-Cl6 120.24 119.727 S42-C45-C47 118.11 120.295 C52-C56-C65 108.85 109.403
C15-C18-H2I 119.9 119.936 C46-C45-C47 120.54 121.294 C57-C56-C6I 109.1 108.197
C16-C18-H2I 119.9 120.337 C45-C46-C48 119.15 119.105 C57-C56-C65 109.1 109.416
C11-O22-C12 117.36 119.470 C45-C46-H49 120.4 120.045 C61-C56-C65 108.1 108.163
C3-N23-C4 115.93 116.655 C48-C46-H49 120.4 120.846 C56-C57-H58 109.5 111.865
C2-N24-C3 116.21 116.568 C45-C47-C50 119.39 118.412 C56-C57-H59 109.5 110.146
C8-N25-C10 116.05 116.947 C45-C47-H51 120.3 120.834 C56-C57-H6O 109.5 110.941

C8-N26-C9 115.46 116.947 C50-C47-H51 120.3 120.726 H58-C57-H59 109.5 107.804
C10-N27-S42 125.60 127.108 C46-C48-C52 121.41 121.478 H58-C57-H60 109.5 107.820
C10-N27-H55 117.2 117.492 C46-C48-H53 119.3 118.037 H59-C57-H60 109.5 108.126
S42-N27-H55 117.2 112.405 C52-C48-H53 119.3 120.485 C56-C61-H62 109.5 109.460
H29-C28-H30 109.5 109.564 C47-C50-C52 121.77 122.187 C56-C61-H63 109.5 111.924
H29-C28-H31 109.5 109.780 C47-C50-H54 119.1 117.855 C56-C61-H64 109.5 111.938
H29-C28-032 109.5 105.961 C52-C50-H54 119.1 119.958 H62-C61-H63 109.5 107.493
H30-C28-H31 109.5 109.761 C48-C52-C50 117.74 117.525 H62-C61-H64 109.5 107.476
H30-C28-O32 109.5 110.342 C48-C52-C56 122.81 122.671 H63-C61-H64 109.5 108.355
H31-C28-032 109.5 111.360 C50-C52-C56 119.46 119.804 C56-C65-H66 109.5 111.934
C13-032-C28 116.32 115.971 C52-C56-C57 109.08 109.164 C56-C65-H67 109.5 110.949
C34-C33-H35 109.8 111.050 C52-C56-C61 112.58 112.451 C56-C65-H68 109.5 110.134
H66-C65-H67 109.5 107.830 H67-C65-H68 109.5 108.083
Table 3 Energetic parameters and global reactivity descriptors of bosentan

Parameters Bosentan
Total Energy (a.u.) -2170.038
Dipole Moment (debye) 6.760
EHOMO (eV) -0.2387
ELUMO (eV) -0.0830

Energy gap (eV) 0.1557
Electron affmity(E) (eV) 0.0830
Ionization Potential (I) (eV) 0.2387
Electronegativity (X) (eV) 0.1609
Chemical hardness (I]) (eV) 0.07784
Chemical Softness (S) (eV"1) 6.4234
Global Electrophilicity(co) (eV) 0.1662
Chemical potential(u)(eV) -0.1609
Global softness(a)(eV"1) 12.8468
ANmax 2.0665

We Claim:

1. An improved process to synthesize dual endothelin receptor antagonist bosentan,
said process comprises:
(a) reacting diethylbromomalonate (III) and 2-methoxy phenol (IV) to obtain diethyl 2-(2-methoxyphenoxy) malonate (V),
(b) reacting diethyl 2-(2-methoxyphenoxy) malonate (V) with pyrimidine-2-carboximidamide salt (VII) in the presence of alkali metal alkoxide and a solvent to obtain 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII),
(c) reacting 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol (VIII) with a
dehydrating agent to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX),
(d) reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (IX) with
4-(tert-butyl) benzene sulfonamide (XI) in the presence of a suitable alkali carbonate and a solvent at specific reaction conditions to obtain 4-(tert-
butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulphonamide (XII),
(e) reacting 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2'-
bipyrimidin]-4-yl) benzene sulphonamide (XII) with ethylene glycol at a
specific temperature ranging from 75 °C to 85 °C, in the presence of a suitable base, alkali metal alkoxide and a transition metal catalyst to obtain crude form of highly pure bosentan, [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2'-bipyrimidin]-4-yl) benzene sulfonamide (I).
2. The process as claimed in claim 1, wherein the alkali carbonate of step is selected
from potassium carbonate, sodium carbonate, cesium carbonate and lithium carbonate or any combination thereof.
3. The process as claimed in claim 1, wherein the solvent is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, n-butanol, dioxane or any combination thereof.
4. The process as claimed in claim 1, wherein the alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, or any combination thereof.
5. The process as claimed in claim 1 wherein said base is selected from acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, acetonitrile, n-butanol, dioxane or any combination thereof.
6. The process as claimed in claim 1 wherein said dehydrating agent is selected from phosphoryl chloride (POCh), phosphoric anhydride (P2O5), 1,3,5-trichlorotriazine.
7. The process as claimed in claim 1 wherein said specific reaction conditions in step (d) are temperature ranging from 80 °C to 120 °C and reaction time between 10 hours to 14 hours.
8. The process as claimed in claim 1 wherein said temperature in step (e) is 80 °C.
9. The process as claimed in claim 2 wherein said alkali carbonates are potassium carbonate or cesium carbonate or a mixture thereof.
10. The process as claimed in 3 wherein said solvent is acetone.
11. The process as claimed in claim 4, wherein said alkali metal alkoxide is lithium t-butoxide.
12. The process as claimed in claim 6, wherein said dehydrating agent is phosphoryl chloride.
13. The process as claimed in claim 7, wherein said specific reaction conditions are temperature of 100 °C for 12 hours.
14. The process as claimed in claim 1, wherein the transition metal catalyst in step (e) is copper iodide.
15. The process as claimed in claim 1, wherein yield of said crude bosentan is 93.35% or more.
16. The process as claimed in claim 1, wherein purity of said crude bosentan is 92.87% or more.
17. The process as claimed in claim 1, wherein said crude bosentan is crystallized to obtain pure bosentan using a polar aprotic solvent, a polar protic solvent or their mixtures.
18. The process as claimed in claim 17, wherein said polar aprotic solvents are selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate tetrahydrofuran or any combination thereof.
19. The process as claimed in claim 18, wherein said polar aprotic solvent is ethyl acetate.
20. The process as claimed in claim 17, wherein the polar protic solvents are selected from water, ethanol, methanol, ammonia, acetic acid, or any combination thereof.
21. The process as claimed in claim 20, wherein the polar protic solvent is methanol.
22. The process as claimed in claim 17, wherein the pure Bosentan is more than 99.9% pure.
23. The process as claimed in claim 16, wherein the pure Bosentan is 100% pure.
24. The process as claimed in claim 16 wherein yield of pure bosentan is 81.05 % or more.
25. The process as claimed in claim 1, wherein the Bosentan obtained is free from bis sulfonamide impurity.
26. A pharmaceutical composition comprising Bosentan capable of being used in endothelin-receptor mediated disorders.