Field of the invention:

The present invention relates to an improved process for the preparation of Bosentan. Bosentan is chemically known as 4-tert-butyl-N-(6-(2-hydroxyethoxy)-5-(2- methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzensulfonamide having the structural formula-1.

Bosentan is found to be a potential inhibitor of endothelin receptor. Endothelin receptor 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 receptor especially Bosentan, and therefore considered to represent a new approach to the treatment of pulmonary hypertension. The selective non-peptide 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 is disclosed in US patent No. 5,292,740. The disclosed process for the preparation of bosentan involves condensation of N-(6- chloro-5(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-4-tertiarybutyl benzene sulfonamide and sodium ethylene glycolate in ethylene glycol at 110°C. The said patent involves the usage of monoanion ethylene glycol leads to the formation of undesired ethylene glycol bisulfonamide, in which two molecules of the pyrimidine monohalide coupled with one molecule of ethylene glycol. The said ethylene glycol bisulfonamide is known as dimer impurity. The other impurity is digol dimer impurity, which is formed due to the presence of digol impurity in ethylene glycol. The said dimer impurities are represented by the following structural formula.

The removal of bis-sulfonamide compound required costly and laborious separation steps to obtain a pharmaceutically suitable pure ethylene glycol sulfonamide compound. Generally the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation. Hence this process is commercially not suitable.

US 6136971 disclose a process for the preparation of ethylene glycol sulfonamide derivatives including bosentan. The disclosed process involves the reaction of p-tert- butyl-N-[6-chloro-5-(0-methoxy-phenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide potassium salt with ethylene glycol mono-tert-butyl ether in presence of a base provides the p-tert-butyl-N[6-(2-tert-buyl-ethoxy)-5-(0-methoxy-phenoxy)[2,2'-bipyrimidin]-4- yl]benzenesulfonamide, which on hydrolysis with formic acid to provide bosentan formate. The obtained bosentan formyl derivative on treatment with a base to provide bosentan. The main disadvantages of the said process are that, using mono-protected ethylene glycol sulfonamide requires additional deprotection step so that number of reaction steps are increased. Hence the process is more time consuming, laborious, involves usage of more reagents and solvents, decreased yields, which increases the overall cost of the product.
WO 2009/95933 discloses a process for the preparation of bosentan, which involves the reaction of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene-sulfonamide with sodium hydroxide in ethylene glycol at 160- 165°C for longer hours to provide the p-tert-butyl-N-[6-(hydroxyl)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide, which on reaction with 2-choroethanol in dimethyl formamide in presence of sodium carbonate to provide bosentan. The said process involves the usage of ethylene glycol and reaction carried out at 160-165°C and hence commercially not recommendable. Even though the said application disclose the use of toluene in place of ethylene glycol it does not specifically exemplified the process parameters and has been carried out in analogous maimer to the one exemplified in ethylene glycol.

There is a need in the art for the preparation of bosentan which avoids the usage of ethylene glycol or its protected derivative and to perform in an industrial scale having less number of steps and isolation.

Summary 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-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2 with 2-chloroethan-l-ol or 2-bromoethanol in the presence of suitable base, in a suitable solvent to provide the bosentan compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- yl)-benzene sulfonamide compound of formula-2 which comprises of reacting the 4-tert- butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3 with a base in a suitable solvent to provide the compound of formula-2.

Advantages of the present invention:

• The present invention avoids the usage of ethylene glycol as a solvent and thereby avoids problems associated with the prior art processes.
• Involves the usage of toluene, DMSO in place of ethylene glycol reduces amount of heat required for its removal and also reduces the cost of production.
• The present invention avoids the formation of dimer & digol dimer impurities and therefore having high purity.
• It is eco-friendly and cost effective process.
Detailed description of the invention:
Accordingly 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-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2

with 2-chloroethan-l-ol or 2-bromoethan-l-ol in the presence of base and in a suitable solvent to provide bosentan compound of formula-1, characterized in that the suitable solvent used is selected from a mixture of toluene/DMSO or toluene/DMF. The reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent.

The second aspect of the present invention provides an improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)- benzene sulfonamide compound of formula-2,

which comprises of reacting the 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3

with a suitable base selected from sodium hydroxide, potassium hydroxide preferably sodium hydroxide in a suitable solvent to provide the 4-tert-butyl-N-(6-hydroxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2, characterized in that the suitable solvent is a mixture of toluene, dimethyl sulfoxide and water or mixture of dimethyl sulfoxide and water. The reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent. The base used in the reaction is about 2-7 moles w.r.to 4-tert-butyl- N-(6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3.

In the reported process of WO 2009/095933, the conversion of 4-tert-butyl- N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide to 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide involves the usage of ethylene glycol as a solvent which leads to the formation of dimer & digol dimer impurities. Where as in the present invention of bosentan, ethylene glycol replaced with a mixture of toluene, dimethylsulfoxide and water. Hence the present invention avoids the formation of dimer impurity, digol dimer impurity and other possible degradation impurities observed due to the high temperature required for the removal of ethylene glycol. Hence the compound of formula-2 free of dimer and digol dimer impurities and using the same in the preparation of bosentan with high purity with the absence of dimer impurity and digol dimer impurity.

Moreover as per the process disclosed in the above application for the preparation of bosentan, N-alkylated impurity having the following structure formed in the ratio of 10-15% and its has been removed by purification, whereas in the present invention N- alkylated impurity is formed at the level of less than 3% and washed out less than 0.1% by HPLC, preferably less than 0.05 % by purification of bosentan from a mixture of ethylacetate and aqueous methanol.

N-alkylated impurity
Further bosentan prepared by the present invention is substantially free of dimer impurities i.e. dimer impurity and digol dimer impurity as measured by HPLC.
The starting material of the present invention can be prepared by the process known in the art or can be prepared from the process disclosed in US 5292740 & WO 2009/095933.
Bosentan prepared according to the present invention is further converted into bosentan monohydrate by recrystallisation from ethanol/water or by the methods known in the art.

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 CI 8, 250 X 4.6 mm, 5|im or Equivalent; Flow rate : 0.8 ml/min.; Wave length: 220 nm.; Temperature : 30°C; Load: 20 nl using aqueous methanol and aqueous methanolic dipotassium hydrogen orthophosphate in ratio of 1:1 as a diluent.

The present invention schematically represented as follows:
The present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example 1: Preparation of 4-tert-butyI-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2:
A mixture of toluene (175 ml), DMSO (75 ml), water (50ml), Sodium hydroxide (15.2 grams) and 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)- benzene sulfonamide (50 grams) was heated to 105-110°C and the reaction mixture stirred for 12-13 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Water (400 ml) was added to the reaction mixture and stirred for 10 minutes. Acidified the reaction mixture with Conc.HCl and filtered the obtained solid, washed the solid with water. Methanol (75 ml) was added to the obtained solid at 25-30°C and stirred for 1 hour. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 38 grams

Example-2: Preparation of bosentan compound of formula-1:
A mixture of DMSO (125 ml), toluene (125 ml), sodium carbonate (20.9 grams) and 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide (25 grams) was heated to 105-110°C and stirred for 3.5-4 hours at same temperature. 2-chloro ethanol (35.72 grams) was added to the reaction mixture at 105- 110°C and stirred it for 12-13 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 300 ml of water was added to it.

Acidified the reaction mixture with Cone. HCL at room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and distilled off the organic layer under reduced pressure. Methanol (25 ml) was added to the obtained residue at 25-30°C and stirred the reaction mixture for 30 minutes. Filtered the obtained solid, washed with methanol and dried to get the title compound. Yield: 20.5 grams Purity by HPLC: 97.15% N-alkylated impurity: 1.46% (by HPLC)
Example-3: Purification of Bosentan compound of formula-1
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml), 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: 99.82%; N-alkylated impurity: 0.01%
Example-4: Preparation of Bosentan monohydrate:
A mixture of Bosentan (10 grams) and ethanol (20 ml) was heated to reflux temperature and stirred at reflux for 30 minutes. Water (30 ml) was slowly added and the reaction mixture was cooled to 25-30°C and stirred for 6 hours. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 10 grams
Purity by HPLC: 99.90%; N-alkylated impurity: < 0.01%

We claim:

1. An improved process for the preparation of bosentan compound of formula-1,
which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2
with 2-chIoroethan-l-ol or 2-bromoethan-l-ol in the presence of base and a suitable solvent to provide bosentan compound of formula-1, characterized in that the suitable solvent used is selected from a mixture of toluene/DMSO or toluene/DMF.

2. An improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2,which comprises of reacting the 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3 with a suitable base selected from sodium hydroxide or potassium hydroxide in a suitable solvent to provide the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2, characterized in that the suitable solvent is selected from a mixture of toluene, dimethyl sulfoxide and water or mixture of dimethyl sulfoxide and water.

3. A process according to any of the preceding claims, wherein the reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent used.

4. A process for the preparation of bosentan of claim 1, further comprises of slurrying the bosentan in a suitable alcoholic solvent to reduce the amount of N-alkylated impurity.

5. A process according to claim 2, wherein the base used in the reaction is about to 2 to 7 moles w.r.to 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- yl)-benzene sulfonamide compound of formula-3.

6. The use of mixture of toluene, dimethylsulfoxide and water for the conversion of 4- tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide in to 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide.

7. A process for the preparation of bosentan compound of formula-1, which comprises of preparing the compound of formula-2 according to claim-2, and converting the same into bosentan.

8. A process according to any of the preceding claims, wherein the obtained bosentan is substantially free of dimer and digol dimer impurities and having purity greater than 99.50% by HPLC.

9. Bosentan and 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- yl)-benzene sulfonamide substantially free of dimer impurity and digol dimer impurity.

10. A process according to claim 1 or 7, wherein the bosentan is further converted into bosentan monohydrate using ethanol/water and the obtained bosentan monohydrate containing less than 0.05% of N-alkyl impurity; preferably less than 0.02% by HPLC and free of dimer and digol dimer impurities.