This application claims priority to Indian patent application No. 3030/CHE/2010 filed on Oct 13, 2010 and 3920/CHE/2010 filed on Dec 22, 2010

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Bosentan or its salt. The present invention also relates to an improved process for the deprotection of hydroxy protected Bosentan. The present invention further relates to a pharmaceutical composition comprising Bosentan of formula I with excipients.

BACK GROUND 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 is chemically known as 4-(1,1-Dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide, having structural formula I.

Bosentan and its analogues as potential endothelin inhibitors have been first disclosed in US patent No. 5292740. The patent also disclosed the methods for preparing these compounds.

One of the methods involves the dichloro derivative is reacted with 4-tert-butylbenzenesulfonamide and one of the chlorine is replaced by 4-tert-butylbenzenesulfonamide. The sulfonamide derivative thus formed is reacted with ethylene glycol in presence of sodium to provide bosentan sodium salt (Scheme 1).

The 740 patent describes the use of sodium metal for the preparation of sodium ethylene glycolate. Sodium metal is an explosive and hazardous reagent and vigorously reacts with water. Moreover, the bosentan obtained by the process described in the 740 patent using sodium metal is not satisfactory from a purity perspective. Unacceptable amount of impurities are formed along with Bosentan.

Organic Process Research & Development 2002, 6, 120-124 discloses that the Bosentan obtained as per process described in US 740 patent is generally not of satisfactory purity. Unacceptable amount of impurities are generally formed along with Bosentan. The product formed by this method requires three more crystallizations to provide specification grade Bosentan suitable for formulation.

Based on the prior art disadvantages there is need for alternative process to obtain a pure Bosentan.The present invention encompassed herein an improved, commercially viable and industrially advantageous process for the preparation of Bosentan. The current processes solve the drawbacks associated with the prior processes and it is commercially viable for preparing Bosentan.

US 6136971 discloses a process for the preparation of Bosentan wherein 4,6-dichloro- 5-(2-methoxyphenoxy)-2,2'-bipyrimidine reacted with 4-tert-butylbenzenesulfonamide in the presence of anhydrous potassium carbonate and a phase transfer catalyst (e.g., benzyltriethylammonium chloride) in toluene, provides p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt. The potassium salt is then reacted with ethylene glycol mono-tert-butyl ether in toluene in the presence of sodium hydroxide to produce p-tert- butyl-N- [6-(2-tert-butyl-ethoxy)-5-(2-methoxyphenoxy) [2,2 '-bipyrimidin] -4-yl]benzenesulfonamide (Bosentan tert-butyl ether). The Bosentan tert-butyl ether is then subjected to deprotection with formic acid afford formyl derivative of Bosentan. This formyl derivative is reacted with sodium hydroxide in mixture of ethanol and water followed by acidification with hydrochloric acid to give crude Bosentan. The crude Bosentan is further purified in mixture of ethanol and water to give Bosentan monohydrate (Scheme 2).

According to US '971 process the deprotection of tert-butyl sulfonamide with formic acid, this leads to formation of formyl impurity. This impurity is difficult to remove in the final Bosentan. It needs number of purification steps in different solvents even though to complete removal of these impurities from final product is not possible.

Based on prior art disadvantages, there is a definite need to develop an alternative process for the deprotection of hydroxy protected Bosentan. The present invention overcomes the difficulties with phosphoric acid for the hydrolysis of hydroxy protected Bosentan.
The removal of protecting groups are performed using suitable deprotecting agents by known methods, for example as disclosed in "Protecting Groups in Organic Synthesis," T.W. Greene, John Wiley & Sons, New York, N.Y., 1981.

Phosphoric acid is considered a green reagent as it is environmental benign worker friendly for the deprotection of tert-butyl carbamates, esters and ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid sensitive-groups. The present invention encompassed herein an improved, simple, commercially viable, eco-friendly and industrially advantageous process over the prior art process for preparation of Bosentan.
The present invention encompassed herein an improved, simple, commercially viable, eco-friendly and industrially advantageous process over the prior art process for preparation of Bosentan.

SUMMARY OF THE INVENTION:

The present invention relates to an improved process for the preparation of Bosentan or its salt thereof.

One aspect of the present invention is to provide an improved process for the preparation of Bosentan of formula I or its salt comprising the steps of: a) reacting dichloro compound of formula VII with ethylenegycol in a solvent in the presence of base to produce monochloro derivative of formula VI, b) reacting monochloro derivative of formula VI with propionyl reagent in a solvent in the presence of base to produce propionyl protected monochloro derivative of formula V, c) reacting the compound of formula V with 4- tertbutyl benzene sulfonamide in a solvent in the presence of a base to produce propionyl protected Bosentan of formula IV, d) hydrolyzing the compound of formula IV to give Bosentan salt of formula III, and e) converting Bosentan salt to Bosentan.

Another aspect of the present invention is to provide novel crystalline Bosentan lithium.
Yet another aspect of the present invention is to provide a process for the preparation of Lithium salt of Bosentan of formula III comprising the steps of: a) reacting hydroxyl protected bosentan with lithium source, and b) isolating crystalline lithium salt of Bosentan formula I.
Yet another aspect of the present invention is to provide a process for the purification of Bosentan from the crude Bosentan comprising the steps of: a) reacting crude Bosentan with pivaloyl chloride in a solvent to obtain pivaloyl derivative of compound of formula Va, b) optionally purify the compound of formula Va, c) hydrolyzing the compound of formula Va, and d) isolating Bosentan formula I.

In another aspect of present invention is to provide a novel 2,2-Dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yloxy]-ethyl ester compound of formula Va.

Yet another aspect of the present invention is to provide an improved process for the preparation of Bosentan comprising the steps of: a) dissolving hydroxy protected Bosentan in a solvent, b) reacting with phosphoric acid, c) treating the compound obtained in step b) with a base, and d) isolating Bosentan.

The present invention is schematically represented by the following scheme 3.

BRIEF DESCRIPTION OF DRAWINGS:

Figure-1: Illustrates the powder X-Ray diffractogram of crystalline Form M of Bosentan
lithium salt.

Figure-2: Illustrates the TGA of crystalline Form M of Bosentan lithium salt.

Figure -3: Illustrates the DSC of crystalline Form M of Bosentan lithium salt.

DETAILED DESCRIPTION OF THE INVENTION:

Present invention relates to an improved process for the preparation of Bosentan or its salt, wherein dichloro compound is reacted with ethyleneglycol in a solvent to produce monochloro derivative. The monochloro derivative is reacted with propionyl reagent in a solvent to produce propionyl protected monochloro derivative. Upon reaction with 4- tertbutyl benzene sulfonamide in a solvent to produce propionyl protected Bosentan, followed by hydrolysis to give Bosentan.

One embodiment of the present invention is to provide an improved process for the preparation of Bosentan of formula I or its salt comprising the steps of:

a. reacting dichlorocompound of formulaVII

With ethylenegycol in a solvent in the presence of base to produce monochloro derivative of formula VI,

b. reacting monochloro derivative of formula VI with propionyl reagent in a solvent in the presence of base to produce propionyl protected monochloro derivative of formula V,

c. reacting the compound of formula V with 4- tertbutyl benzene sulfonamide in a solvent in the presence of base to produce propionyl protected Bosentan of formula IV,

d. hydrolyzing the compound of formula IV to give Bosentan salt of formula III,
and

e. converting Bosentan salt to Bosentan.

According to the present invention dichloro compound of formula VII is reacted with ethylene glycol in a solvent selected form tetrahydrofuran, dimethylformamide, dimethylacetamide or methyl tert-butyl ether, preferably tetrahydrofuran in the presence of base selected from sodium hydroxide potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, preferably sodium hydroxide. The reaction is optionally carried out by lot wise addition of base at a temperature ranging from 0-35°C, preferably 20-35°C.

According to present invention, protection of monochloro derivative of formula VI is done with propionyl reagent selected from propionic anhydride or propionyl chloride in a solvent selected from toluene, xylene, acetonitrile, acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran or methyl isobutyl ketone, preferably dimethyl acetamide. The reaction is carried out in the presence of base selected from organic bases such as triethylamine or inorganic base such as sodium hydroxide. The reaction temperature is ranging from 25-90°C and duration of the reaction is about 6-7 hours. The compound of formula V is isolated by saturating the reaction mass with water and the separating the solid by filtration to get compound of formula V.

According to present invention, compound of formula V is reacted with 4-tert-butyl benzene sulfonamide in a solvent selected from dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or methyl isobutyl ketone, preferably dimethyl acetamide in the presence of base is selected from alkaline earth metal hydroxides such as sodium hydroxide, alkaline earth metal carbonate such as sodium carbonate or alkaline earth metal phosphate such as potassium phosphate.

According to the present invention, hydrolysis reaction of formula IV is carried out in a solvent selected from tetrahydrofuran, methanol, ethanol, isopropanol, acetone, acetonitrile, toluene or xylene, preferably tetrahydrofuran. Hydrolysis is carried out with acid or base. The acid is selected from phosphoric acid, trifluoroacetic acid, formic acid or hydrochloric acid and the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide,
sodium carbonate, potassium carbonate or lithium carbonate to get its corresponding Bosentan salt of formula III.

According to the present invention, the bosentan salt of compound formula III is converted to Bosentan by treating with acid such as hydrochloric acid in a solvent selected from methanol ethanol, isopropanol, acetone, acetonitrile, ethyl acetate or dichloromethane.
Another embodiment of the present invention is to provide Bosentan salt as a crystalline solid.
Yet another aspect of the present invention is to provide a novel crystalline form-M of Bosentan lithium salt, characterized by an X-Ray diffraction pattern having the 26 values at 6.30, 10.11, 12.61, 14.44, 18.92, 23.23 and 25.29 ± 0.2.

Yet another aspect of the present invention is to provide novel crystalline form-M of Bosentan lithium, characterized by a DSC comprising an endothermic peak at about 119°C and an endothermic peak at about 203°C.

Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Bosentan lithium salt comprising the steps of:

a. reacting hydroxyl protected bosentan with lithium source, and
b. isolating crystalline Bosentan lithium.

According to the present invention hydroxyprotected bosentan is reacted with lithium source selected from lithium hydroxide or lithium carbonate in a solvent selected form methanol, ethanol, isopropanol, tetrahydrofuran, acetone or acetonitrile. The obtained solid is filtered.

Another embodiment of the present invention is to provide a process for the purification of Bosentan, which comprising the steps of:

a) reacting crude Bosentan with pivaloyl chloride in a solvent to obtain compound of formula Va,
b) optionally purifying the compound of formula Va,
c) hydrolyzing the compound of formula Va, and
d) isolating Bosentan.

According to the present invention crude Bosentan is reacted with pivaloyl chloride in a solvent at 15-35°C, preferably 20-25°C for about 12-20 hours. After completion of the reaction hydrocarbon solvent is added and the solid is separated by filtration. This solid is refluxed in a solvent, cooled to 0-10°C and the obtained pure solid of formula Va is isolated by filtration. Compound of formula Va is hydrolyzed in the presence of aqueous base in a solvent and finally the obtained Bosentan is treated with aqueous alcohol to get Bosentan.

According to the present invention Bosentan is reacted with pivolyol chloride in a solvent selected from halogenated hydrocarbon such as dichlormethane, aromatic hydrocarbon such as toluene. The hydrocarbon solvent used for the isolation of compound of formula Va is selected from cyclohexane, n-hexane, heptane or pentane.

According to the present invention the solvent used in the purification of compound of formula Va is selected from methanol, ethanol, isopropanol or butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

According to the present invention base used for the hydrolysis is selected from metal hydroxides such as sodium hydroxide, metal carbonates such as sodium carbonate or metal bicarbonates such as sodium bicarbonate.

Yet another embodiment of present invention is to provide novel 2,2-Dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-yloxy]-ethyl ester compound of formula Va, which is characterized by 1H-NMR.

Yet another embodiment of the present invention is to provide an improved process for deprotection of hydroxy protected Bosentan of formula I comprising the steps of:
a) dissolving hydroxy protected Bosentan of formula II
OwP

Where in Z is hydroxy protected group in a solvent,

b) reacting with phosphoric acid,
c) treating the compound obtained in step b) with a base, and
d) isolating Bosentan of formula I.

According to the present invention hydroxy protected Bosentan of formula II is dissolved in a solvent and phosphoric acid is added slowly at room temperature. The resulting solution is heated to reflux for about 3 to 8 hours, preferably about 5 to 7 hours. After completion of reaction the solution is cooled to about 5 to 10°C and water is added, stirred and obtained solid is filtered to afford Bosentan. A hydroxy protecting group is selected from the group consisting of C1-C4 alkyl, acetyl, tert-butyl, silyl and formyl, in particular tert-butyl.
The solvent used for the dissolution of hydroxy protected Bosentan is selected from methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, toluene, xylene, tetrahydrofuran, water or mixture thereof, preferably acetonitrile and the base is selected from alkali or alkaline earth metal hydroxide, carbonate and bicarbonate.

According to the present invention the phosphoric acid used for the reaction is about 5-20 equivalents with respect to hydroxy protected Bosentan of formula II, more preferably 10-15 equivalents.

According to the present invention the obtained Bosentan is purified by converting the crude
Bosentan to alkaline salt such as sodium or potassium salt, followed by neutralization to get
Bosentan.

According to the present invention crude Bosentan may be having the purity up to 98.5%.
According to the present invention Bosentan having the purity more than 99.0%, preferably more than 99.5%, more preferably more than 99.95%.

Yet another embodiment of the present invention is to provide pharmaceutical composition comprising: (a) a therapeutically effective amount of Bosentan of formula-1 or pharmaceutically acceptable salt; and (b) at least one pharmaceutically acceptable carrier.
The present invention is illustrated in more detail by the following Examples but should not be construed to be limited thereto.

ADVANTAGES OF PRESENT INVENTION

a) Lithium salt of Bosentan obtained by hydrolysis using Lithium hydroxide is highly pure and need not be crystallized; it is used as such for converting Bosentan.

b) We have observed formation desmethyl impurity when sodium hydroxide is used for hydrolysis. When using Lithium hydroxide does not form this impurity in the reaction.

c) The present invention provides Bosentan free of all the impurities, particularly formyl and tert-butyl impurities.

d) The present invention does not involve explosive chemicals like sodium metal.

EXPERIMENTAL SECTION Powder X-ray Diffraction (PXRD)
XRPD instrument make: Bruker D8 Advance with theta/theta configuration

Detector: Lynx-Eye

X-ray: Cu x-ray tube with generator settings of 40kV and 40mA

29 range: 3.0°-50.0° Step size: 0.05° Time per step: 1sec DSC:

Instrument make: Perkin Elmer Pyris 6 DSC Method programme: 25.0°C- 250.0°C @10.0°C
TGA:

Instrument make: Perkin Elmer Pyris 1 TGA Method programme: 25.0°C- 250.0°C @10.0°C

Examples:

Example 1: Preparation of 2-[6-Chloro-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-
yloxy]-ethanol compound of formula VI.

4,6-dichloro-5(2-methoxyphenol) [2,2 ] bipyrimidinyl of formula VII (100g,1eq) was taken in tetrahydrofuran (500ml,5Vol) and ethylene glycol (1L,10Vol) was added at 20-25°C. Cooled the mass to 0 to 5°C and sodium hydroxide (5.73g, 0.5eq) was added, stirred for 15min and added second lot of sodium hydroxide (5.73g, 0.5eq). Stirred for 15 min and added third lot of sodium hydroxide (5.73g, 0.5eq). Stirred for 1 hour at 0 to 5°C. Allowed to warm to 20-25°C and stirred for 3-4 hours. After completion of reaction, cooled the reaction mixture to 5 to 10°C and water (2L, 20Vol) was added. Stirred for 1 hour, filtered the solid, washed with water (500ml, 5Vol) and dried the solid under vacuum at 55-60°C to get title compound (Yield- 90g, HPLC purity- 98.5%).

Example 2: preparation of Propionic acid 2-[6-chloro-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-yloxy]-ethyl ester compound of formula V.

2-[6-Chloro-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yloxy]-ethanol of formula VI (100g, 1eq), propionic anhydride (68.5ml,2eq) and triethyl amine (74.5ml,2eq) were taken in toluene (500ml, 5vol) at 20-25°C. The reaction mass was heated at 85-90°C for 6-7 hours and the mass was cooled to 0-5°C, water (500ml, 5vol) was added, the resulting mixture was stirred for 1 hour, filtered the obtained solid and washed with water (500ml, 5Vol) and then with toluene (200ml, 2vol). Dried the solid under vacuum at 55-60°C to get title compound (Yield-90g, HPLC purity-99%)

Example 3: Preparation of propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2, 2'] bipyrimidinyl-4-yloxy]-ethyl ester compound of formula IV.
A mixture of 4-tert butyl benzene sulfonamide (49.5g, 1eq), Potassium phosphate (123.8g, 2.5eq) dimethyl acetamide (500ml,5vol) was heated to 40°C and maintained for 30-60 minutes. Propionic acid 2-[6-chloro-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidinyl-4-yloxy]-ethyl ester of formula V (100g, 1 eq) was added to the reaction mixture and the reaction mass was heated to 90°C for 24-28 hours. Filtered the inorganic solid and washed the solid with dimethyl acetamide (100ml, 1vol). To the mixture of water (2.5L, 25vol) and concentrated hydrochloric acid (150ml, 1.5Vol) was added the filtrate at 0-5°C. Maintained the stirring for 1-2 hours at 0-5°C .Filtered the solid and washed with water (500ml, 5vol).Dissolved the wet cake in DCM (500ml, 5Vol) and added to a mixture of water (700ml,7vol) and concentrated hydrochloric acid (75ml, 0.75vol) at 10-15°C.Stirred, separated the DCM layer and repeated the washing with mixture of water (700ml, 7vol) and concentrated hydrochloric acid (75ml, 0.75vol) at 10-15°C. Separated the DCM layer and washed with water (500ml, 5vol). Distilled DCM under vacuum at 35-40°C to get title compound (yield 110g, HPLC purity-85%).
Example 4: Preparation of Bosentan lithium form-M.

Mixture of propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2, 2'] bipyrimidinyl-4-yloxy]-ethyl ester of formula IV (100g, 1eq) and Tetrahydrofuran (600ml, 6Vol) was cooled to 0-5°C. lithium hydroxide monohydrate (20.6g, 3eq) in water (100ml, 1Vol) solution was added dropwise at below 10°C and the reaction mixture was heated to 45-50°C for 5-6 hours. The mass was cooled to 20-25°C and maintained for 4-5 hours. Filtered the solid and washed with tetrahydrofuran (100ml, 1Vol) to get title compound (yield-70g, HPLC purity- 98.5%).

Example 5: Preparation of Bosentan lithium form-M.

Mixture of propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2, 2'] bipyrimidinyl-4-yloxy]-ethyl ester of formula IV (100g, 1eq),tetrahydrofuran (600ml, 6Vol) and Ethanol (200ml, 2Vol) was cooled to 0-5°C and lithium hydroxide monohydrate (20.6g, 3eq) in water (100ml, 1Vol) solution was added drop wise maintaining temp below 10°C.Stirred the reaction mixture at 25-30°C for 24 hours. Filtered the solid and washed with tetrahydrofuran (100ml, 1Vol) to get title compound (yield -60g, HPLC purity-98.5%).

Example 6: Preparation of Bosentan.

Mixture of Lithium salt of Bosentan of formula III (100g, 1 eq) and methanol (1L, 10Vol) was cooled to 5-10°C. 1:1 mixture of concentrated hydrochloric acid and water (40ml, 0.4Vol) solution was added drop wise and stirred at 55-60°C for 30 -60 minutes. Water was added (1L, 10Vol) dropwise at 55-60°C and stirred at 5-10°C for 1-2 hours. Filtered the solid and washed with water (300ml, 3Vol). Dried the solid under vacuum at 55-60°C to get title compound (yield -85g, HPLC purity-99%).

Example 7: p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide formula Via.

The compound of formula VII (500g, 1.0eq), 4-tert butyl benzene sulfonamide (305.2g, 1.0eq) and potassium carbonate (237.24g, 1.2eq) was heated in dimethylsulfoxide (2500.0ml, 5.0vol) at 120°C for 10-12 hours. After completion of reaction, the reaction mixture was cooled to 20°C-25°C and filtered. Filtrate was added to a mixture of water (6000.0ml, 12.0vol) and concentrated hydrochloric acid (100ml, 0.2vol) at 5°C-10°C. After completion of addition the reaction mixture was maintained at 5°C-10°C for 1 hour. Precipitated solid was filtered and washed with water (5000ml, 10.0vol). Dried the solid at 55°C-60°C for 20Hrs under vacuum to get title compound (Yield: 742.Og, 98.67%, HPLC purity 87.39).
The dried solid (742.Og, 1eq) was heated in ethyl acetate (7420.0ml, 10.0vol) at 75°C-80°C for 1 hour. Cooled to 5-10°C and filtered. Washed with ethyl acetate (371.0ml, 0.5vol) and dried the solid under vacuum at 55-60°C for 15hrs. Yield : 556.5g (75%, HPLC purity 99%).
Example 8: Preparation of crude Bosentan from compound of formula Via.

The compound of formula Via (130.0g,1.0eq), ethylene glycol (1470.0ml, 107.0eq) and sodium hydroxide (88.9g, 9.0eq) were heated in tetrahydrofuran (1560.0ml, 12.Ovol) at 60-65°C for 12hours. After completion of reaction, the reaction mixture was added to a mixture of water (4450.0ml,35.0vol) and DL-Tartaric acid (185.0g, 5.0eq) at 5-10°C.Maintained at this temperature for 1 hour. Filtered the solid and washed with water (1300.0ml). Dried the solid, Bosentan, under vacuum at 50-55°C for 12 hours to get the title compound (Yield: 134.5g (95.7%, HPLC purity 98.41%).

Example 9: Preparation of 2,2-Dimethyl-propionic acid 2-[6-(4-tert-butyl-benzenesulfonylamino)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yloxy]-ethyl ester compound of formula Va.

Crude Bosentan (100.0g, 1eq) is obtained in example 9 was taken in dichloromethane (600ml, 6.0vol) at 20-25°C and stirred for 1 hour. Filtered and to the filtrate was added Pivaloyl chloride (300.0ml, 3.0vol). Stirred at 20-25°C for 15 hours. After completion of reaction, charged cyclohexane (1000.0ml, 10.0vol) and stirred for 1 hour. Filtered the solid and washed with cyclohexane (300.0ml, 3.0vol). Dried the solid under vacuum at 50-55°C for 15 hours to get title compound (Yield: 109.0g (97.5%, HPLC purity 95.93%). Impurities are unreacted Bosentan (3.0%) and impurity at RRT 3.31 (0.3%). Characterization of compound of Formula Va was confirmed by 1H-NMR 1H-NMR (CDCI3): 51.29 (s,9H), 9.48 (bs,2H), 8.36 (d,2H), 7.93 (bs,1H), 7.45 (d,2H), 7.13-7.04 (m,2H), 6.97 (d,1H), 6.83 (t,1H), 5.07 (m,2H), 4.38 (m,2H), 3.93 (s,3H) and 1.13 (s,9H).

Example 10: Purification processes of pivaloyl derivative of formula Va.

Crude compound of formula Va (109.Og, 1.0eq), methyl ethyl ketone (1090.0ml, 10.0vol) and ethanol (1090.0ml, 10.0vol) were heated to reflux till clear (around 30 min). Cooled to 5-10°C and maintained for 1 hour. Filtered the solid and washed with ethanol (109.0ml, 1vol). Dried the solid under vacuum at 50-55°C for 3-5hrs (Yield: 50.0g (45.8%, HPLC purity 98.41%). Impurities are unreacted Bosentan (2.7%) and impurity at RRT 3.31 (0.05%).
Example 11: Purification processes of pivaloyl derivative of formula Va.

Crude compound of formula Va (2.0g, 1.0eq) and methanol (20.0ml, 10.0vol) were heated to reflux till clear. Cooled to 5-10°C and maintained for 1 hour. Filtered the solid. Dried the solid under vacuum at 50-55°C for 3-5hrs (Yield: 1.4g (70%, HPLC purity 98.17%). Impurities are unreacted Bosentan (1.23%) and impurity at RRT 3.31 (0.03%).

Example 12: Purification processes of pivaloyl derivative of formula Va.

Crude compound of formula Va (1.0g, 1.0eq) and acetonitrile (5.0ml, 5.0vol) were heated to reflux for 30 min (slurry). Cooled to 25-30°C and maintained for 1 hour. Filtered the solid. Dried the solid under vacuum at 50-55°C for 3-5hrs (Yield: 0.8g (80%), HPLC purity 97.37%). Impurities are unreacted Bosentan (1.96%) and impurity at RRT 3.31 (0.04%).

Example 13: Preparation of Bosentan from compound of formula Va.

Compound of formula Va (50.0g,1.0eq) and ethanol (850.0ml, 17.Ovol) slurry was cooled to 10-15°C and sodium hydroxide (22.0g,7.0eq) in water (100.0ml,2.Ovol) solution was added. Allowed to attain 20-25°C and stirred at that temperature for 7-10 hours, till completion of reaction. Cooled to 10-15°C and added a 1:1 mixture of concentrated hydrochloric acid and water (60.0ml, 1.2vol). Stirred at 10-15°C for 1hour. Added water (850.0ml, 17vol) and stirred for 1 hour. Filtered the solid and washed with water twice (500.0ml). Dried the solid under vacuum at 50-55°C for 7hrs to get title compound of formula I (Yield: 40.Og (80%), HPLC purity 99.31% and Impurity at RRT 3.31 is 0.06%).

Example 14: hydrolysis of tert-butyl protected Bosentan of formula II

Tert-butyl protected Bosentan of formula II (10g, 1 eq) was taken in Acetonitrile (100ml, 10 vol) and phosphoric acid (24.21g, 15 eq) was added in three lots at 25-35°C. Refluxed for about 5-7 hours till completion of reaction. After completion of reaction, cooled the reaction mixture to 5-10°C and water (100ml, 10vol) was added slowly. Stirred for 1 hour at 5-10°C and filtered the precipitated solid. Washed the solid with water and dried under vacuum to get Bosentan (Yield: 9g; HPLC purity: 98.5%).

Example 15: hydrolysis of tert-butyl protected Bosentan of formula II

Tert-butyl protected Bosentan of formula II (10g, 1 eq) was taken in Acetonitrile (100ml, 10 vol) and phosphoric acid was added in three lots at reflux temperature in different intervals. Maintained the reaction for 5-7 hours at reflux temperature till completion of reaction, after completion of reaction, cooled the reaction mixture to 5-10°C and water (100ml, 10vol) was added slowly. Stirred for 1 hour at 5-10°C and filtered the precipitated solid. Washed the solid with water and dried under vacuum to get Bosentan (Yield: 9g; HPLC purity: 98.5%). Example 16: Purification of Bosentan.

Bosentan (9g, 1eq obtained from Example 15) was taken in Ethanol (99ml, 11 vol) and the slurry was cooled to 10-15°C. Solution of Sodium hydroxide (1.89g,3eq) in water (9ml,1vol) was added slowly at 10-15°C and the solution was stirred at 20-25°C for 2-3 hours. The precipitated solid was filtered, washed with ethanol (27ml, 3vol) and suck dried. The solid was suspended in ethanol (63ml, 7vol) and cooled to 10-15°C. Acidified the reaction mass with a mixture of concentrated hydrochloric acid (1.8ml,0.2vol) and water (0.9ml,0.1vol) maintaining temperature 10-15°C.Water (63ml,7vol) was added slowly at 10-15°C.Stirred for

1 hour at the same temperature. Filtered, washed with water and dried under vacuum to get Bosentan of formula I (Yield 7.2g, HPLC purity 99.3%).

Example 17: Preparation of Bosentan monohydrate.

The mixture of Bosentan (100g, 1eq) and methanol (700ml, 7Vol) was heated to reflux and water (10ml, 0.1 Vol) was added at reflux to get a clear solution. Filtered the clear solution at 65°C. Filtrate was heated to reflux to get a clear solution. Water (700ml, 7Vol) was added at reflux temperature, 65-67°C. The slurry was cooled to 0 to 5°C within 1 hour, maintained the stirring for 1 hour at 0 to 5°C and filtered the obtained solid. Washed the solid with water (200ml, 2Vol) and dried under vacuum at 50-55°C for 8 hours to get tittle compound (yield-90gm, HPLC purity-99.5).

CLAIMS:

1. An improved process for the preparation of Bosentan or its salt comprising the steps of:

a) reacting dichloro compound of formula VII

Formula VII with ethylenegycol in a solvent in the presence of a base to produce monochloro derivative of formula VI,

Formula VI

b) reacting monochloro derivative of formula VI with propionyl reagent in a
solvent in the presence of base to produce propionyl protected monochloro
derivative of formula V,

Formula V

c) reacting the compound of formula V with 4- tertbutyl benzene sulfonamide in
a solvent in the presence of base to produce propionyl protected Bosentan
of formula IV,

Formula IV

d) hydrolyzing the compound of formula IV to give Bosentan salt of formula III,

M+ is Na K and Li

Formula III and

e) converting Bosentan salt to Bosentan.

2. The process according to claim 1, wherein the solvent used in step a) is selected from tetrahydrofuran, dimethylformamide, dimethyl acetamide or methyl tert-butyl ether.

3. The process according to claim 1, wherein the base is used in step a) selected from sodium hydroxide potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate.

4. The process according to claim 1, wherein the solvent used in step b) selected from toluene, xylene, methanol, ethanol, isopropanol, acetonitrile, acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran or methyl isobutyl ketone.

5. The process according to claim 1, wherein the base used in step b) is organic bases such as triethylamine, inorganic base such as sodium hydroxide.

6. The process according to claim 1, wherein the propionyl reagent used in step b) selected from propionic anhydride or propionyl chloride.

7. The process according to claim 1, wherein the solvent used in step c) selected from dimethyl acetamide, dimethylformamide, dimethyl sulfoxde, tetrahydrofuran or methyl isobutyl ketone.

8. The process according to claim 1, wherein the base used in step c) selected from alkaline earth metal hydroxides such as sodium hydroxide, alkaline earth metal carbonate such as sodium carbonate or alkaline earth metal phosphate such as potassium phosphate.

9. The process according to claim 1, wherein the solvent used in step d) is selected from tetrahydrofuran, methanol, ethanol, isopropanol, acetone, acetonitrile, toluene or xylene.

10. The process according to claim 1, wherein hydrolysis is carried out in the presence of a base the base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate or in the presence of an acid selected from phosphoric acid, trifuoroacetic acid, formic acid, or hydrochloric acid.

11. Crystalline Form M of Bosentan lithium salt characterized by an X-Ray diffraction pattern comprising 26 values at 6.30, 10.11, 12.61, 14.44, 18.92, 23.23 and 25.29 ± 0.2.

12. A process for the purification of Bosentan, which comprising the steps of:

a) reacting crude Bosentan with pivaloyl chloride to obtain compound of formula Va in a solvent,

b) optionally purifying the compound of formula Va,

c) hydrolyzing the compound of formula Va, and

d) isolating pure Bosentan.

13. The process according to claim 12, wherein solvent selected from halogenated
hydrocarbon such as dichlormethane, aromatic hydrocarbon such as toluene.

14. The process according to claim 12, wherein compound of formula Va is purified in a solvent selected from acetonitrile, methanol, ethanol, acetone, methylethylketone, methyltertiarybutylether, disiopropylether, diethylether or mixture thereof.

15. A compound of formula Va.

16. An improved process for deprotection of hydroxy protected Bosentan comprises the steps of:

a. dissolving hydroxy protected Bosentan of formula II

Where in Z is hydroxy protected group in a solvent,

b. reacting with phosphoric acid,

c. treating the compound obtained in step b) with a base, and

d. isolating Bosentan of formula I.

17. The process according to claim 16, wherein the solvent used for dissolution hydroxy protected Bosentan is selected from methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, toluene, xylene, tetrahydrofuran, water or mixture thereof.

18. The process according to claim 16, wherein the phosphoric acid is used for the reaction is about 5-20 equivalents with respect to hydroxy protected Bosentan of formula II.

19. The process according to claim 16, wherein the base is selected from alkali or alkaline earth metal hydroxide, carbonate and bicarbonate.

20. A pharmaceutical composition comprising: (a) a therapeutically effective amount of Bosentan and (b) at least one pharmaceutically acceptable carrier.