WO2011024056A2

WO2011024056A2 - An improved process for the preparation of bosentan

Info

Publication number: WO2011024056A2
Application number: PCT/IB2010/002090
Authority: WO
Inventors: Kumar Sinha Brajesh; Rajasekhara Raju Konduru; Shankar Reddy Budidet; Pandu Rangarao Vaddi; Islam Aminul; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2009-08-27
Filing date: 2010-08-27
Publication date: 2011-03-03
Also published as: WO2011024056A3

Abstract

The present application provides purification of Bosentan crude by making its crystalline potassium salt, which is further converted to Bosentan (I) with bis-sulfonamide (VIII) and deshydroxyethyl (IX) impurities to less than 0.2% by HPLC analysis.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Bosentan of Formula

(I).

Formula I

BACKGROUND OF THE INVENTION

Bosentan is chemically known as 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2,2']-bipyrimidin-4-yl]benzenesulfonamide.

Bosentan is a specific competitive antagonist at endothelin receptor types ETA and ETβ. Endothelin (ET-I) is a neurohormone, the effects of which are mediated by binding of ETA and ET_B receptors in the endothelium and vascular smooth muscle. ET-I concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role of ET-I . Bosentan has a slightly higher affinity for ET_A receptors than ETB receptors. Bosentan is marketed under the name Tracleer®. It has been approved for the treatment of pulmonary arterial hypertension (PAH).

Bosentan and its pharmaceutically acceptable salts are disclosed in US 5,292,740. US '740 also discloses a process for the preparation of sodium salt of Bosentan (Ia), by reacting 2- amidinopyrimidinium hydrochloride (II) with diethyl-(2-methoxyphenoxy)malonate (III) in the presence of sodium metal in methanol followed by IN sodium hydroxide to produce 5-(2- methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione (IV), which is further reacted with phosphorus pentachloride in presence of N,N-diisopropyl-N-ethylamine to produce 4,6- dichlpro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V). Condensation of 4,6-dichloro-5-(2- methoxyphenpxy)-2,2'-bipyrimidine (V) with 4-(l,l-dimethylethyl)benzenesulfonamide (VI) in the presence of dimethylsulfoxide produce 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2- methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII), which is then reacted with sodium ethylene glycolate in ethylene glycol solvent at 100°C to produce Bosentan as sodium salt (Ia).

The process is as shown in Scheme -I below:

2-Amidinopyrimidinium Diethyl-(2-methoxyphen -2-yl)- hydrochloride malonate

(II) (III)

N,N-Diisopropyl-N- ethylamine/ PCI₅ l)benzene

4-(l,l-dimethylethyl)-N-|6-chloro-5- 4,6-Dichloro-5-(2-methoxyphenoxy)-

(2-methoxyphenoxy)-[2,2'-bipyriπiidin)-4-yl]- 2,2'-bipyrimidine

beπzenesulfonamide

(V)

(VII)

Sodium ethylene glycolate/

Ethylene glycol

Sodium salt of Bosentan

(Ia)

Scheme-I

The major disadvantage with the above process is that the formation of undesired ethylene glycol bis-sulfonamide (VIII) and deshydroxyethyl (IX). The removal of these undesired impurities requires laborious purification steps to produce pharmaceutically suitable pure Bosentan (I). Formula VIII

Formula IX

US 6,136,971 discloses an alternative process for the preparation of Bosentan (I), by condensing 4- (1,1 -dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfo- namide (VII) with mono protected ethylene glycol (X) in the presence of base in aprotic non-polar solvent to produce protected Bosentan (XI). Treating protected Bosentan (XI) with formic acid to produce formyl Bosentan ethanol solvate (XII), which is further treated with base to produce Bosentan (I).

The process is as shown in Scheme -II below:

Base/Aprotic non- polar solvent

4-(l,l-dimethylethyl)-N-|6-chloro-5- tert-butyl ethylene glycol p-tert-butyl-N-|6-(2-tert-butoxyethoxy)-5-

(2-methoxyphenoxy)-|2,2'-bipyrimidiπ|-4-yl| QQ (o-methoxyphenoxy)-2-(pyrimidin- 2-yl)- hen/.enesulfonamide pyrimidin-4-yl| benzeπesulfonamide (VII) (XI)

1. Formic acid

2. Λzeotropic distillation

3. Ethanol

Bosentan (I) Formyl Bosentan

(XII)

Scheme-II

The above process involves multiple steps relating to the protection and de-protection and use of more expensive mono protected ethylene glycol. Hence, the above process is not suitable for commercial scale synthesis of Bosentan (I).

WO 2009/004374 Al discloses a process for the preparation of Bosentan (I), by providing a mixture of ethylene glycol and hydroxide ions, followed by addition of 4-(l,l-dimethylethyl)-N- [6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VIl) and isolating Bosentan (I).

The process is as shown in Scheme -III below:

1. Mixture of ethylene glycol

and hydroxide ions

2. Isolation

(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]- Bosentan (I) benzenesulfonamide

(VII)

Scheme III

When we carried out the reaction of 4-(l,l-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)- [2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VII) with ethylene glycol in the presence of sodium hydroxide to produce Bosentan (I), we have found the formation of about 0.34 % of bis- sulfonamide (VIII) impurity.

WO 2009/095933 Al discloses Bosentan potassium salt, which is prepared by treating Bosentan with 30% aqueous potassium hydroxide in ethanol.

It is difficult to separate the bis-sulfonamide (VIII) and deshydroxyethyl (IX) impurities through crystallization from Bosentan, which typically require repeated crystallizations to achieve_/desired Bosentan purity. The repeated crystallizations add time to the manufacturing process and thus negatively impacts product out put.

Hence, there is a need to develop a purification process, which reduces the unwanted impurities bis-sulfonamide (VIII) deshydroxyethyl (IX) impurities to a pharmaceutically acceptable limit, which in turn provides Bosentan of high purity and improved yield.

The instant invention directed to purification of Bosentan crude by making its crystalline potassium salt, which is further converted to Bosentan (I) with bis-sulfonamide (VIII) and deshydroxyethyl (IX) impurities to less than 0.2 % by HPLC analysis. The present invention also directed to a process for the preparation of Bosentan (I) by using dimethyl-(2-methoxyphenoxy)malonate (XIV).

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide crystalline forms of Bosentan potassium Form I and Form II.

Another objective of the present invention is to provide a process for the preparation of crystalline Bosentan potassium Form I and Form II.

Another objective of the present invention is to provide a simple and cost effective process for the preparation of Bosentan using the above crystalline Bosentan potassium Form I and Form II.

Another objective of the present invention also provides a simple and cost effective process for the preparation of 4-( 1 , 1 -dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrirnidin]-4- yl]benzenesulfonamide (Vila).

SUMMARY OF THE INVENTION

The present invention provides a crystalline Bosentan potassium Form I, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 5.60 ± 0.2, 6.48 ± 0.2, 9.67 ± 0.2, 10.20 ± 0.2, 1 1.16 ± 0.2, 12.89 ± 0.2, 14.04 ± 0.2, 16.80 ± 0.2, 17.89 ± 0.2, 18.80 ± 0.2, 22.38 ± 0.2 two theta degrees.

Another embodiment of the present invention provides crystalline Bosentan potassium Form II, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 6.64 ± 0.2, 8.78 ± 0.2, 9.78 ± 0.2, 10.66 ± 0.2, 14.71 ± 0.2, 17.20 ± 0.2, 17.57 ± 0.2, 18.4 ± 0.2, 22.33 ± 0.2, 27.51 ± 0.2, 29.63 ± 0.2 two theta degrees. Another embodiment of the present invention provides a process for the preparation of crystalline Bosentan potassium Form I,

which comprises:

(i) treating crude Bosentan with potassium hydroxide in aqueous alcohol;

(ii) isolating crystalline Bosentan potassium Form I with less than 0.2 % of bis-sulfonamide impurity (VIII).

Another embodiment of the present invention provides a process for the preparation of crystalline

Bosentan potassium Form II,

which comprises:

(i) acidifying the Bosentan potassium Form I with an acid in DM water;

(ii) basifying the resulting solution of step (i) with aqueous potassium hydroxide; and

(iii) isolating crystalline Bosentan potassium Form II with less than 0.2 % of deshydroxy impurity (IX).

Another embodiment of the present invention provides substantially pure Bosentan having less than about 0.2 % of dimer impurity (VIII) and less than about 0.2 % of deshydroxy impurity (IX).

Formula VIII

Formula IX

Another embodiment of the present invention provides a process for the preparation of substantially pure Bosentan having less then about 0.2% of dimmer impurity (VIII) and less than about 0.2% of deshydroxy impurity (IX),

which comprises :

(i) acidifying the crystalline Bosentan Potassium Form 1 or Form II with an acid in a solvent to produce Bosentan;

(ii) treating the Bosentan obtained from step (i) using the mixture of water and alcohol;

(iii) isolating the Bosentan.

Another embodiment of the present invention also provides a process for the preparation of 4-( 1,1- dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its salt,

Formula Vila

wherein, X represents Cl, Br or I;

which comprises:

(i) treating 2-cyanopyrimidine (XIII),

Formula XIII

using ammonium chloride in the presence of a suitable base in a solvent to produce 2- amidinopyrimidinium hydrochloride of formula II, , Formula II

with the proviso that the base is not sodium mehoxide;

(ii) condensing compound of Formula (II) with dimethyl-(2-methoxyphenoxy)malonate of formula XIV,

Formula XIV

in presence of a suitable base in a solvent to produce 5-(2-methoxyphenoxy)-2- (pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione of formula IV,

Formula IV

with the proviso that the base is not sodium mehoxide;

(iii) treating the compound of Formula (IV) with halogenating agents to produce 4,6- dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine of formula Va,

Formula Va

(iv) condensing the compound of Formula (Va) with 4-(l,l-dimethylethyl)benzene sulfonamide of formula VI, Formula VI

in the presence of base in a solvent optionally in presence of phase transfer catalyst to produce compound of Formula (Vila) or its salts.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the X-ray powder diffraction pattern of crystalline Bosentan potassium Form 1.

Figure 2 illustrates the X-ray powder diffraction pattern of crystalline Bosentan potassium Form

II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5- (2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its salt.

The process comprises, treating 2-cyanopyrimidine (XIII) with a base selected from alkoxides such as sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide and in a solvent selected from lower alkanol such as methanol, ethanol, isopropanol or butanol. The resulting reaction mixture is treated with ammonium chloride to produce 2-amidinopyrimidinium hydrochloride (II).

The reaction can be performed at a temperature ranging from about -10⁰C to about 10⁰C based on the solvents used for the reaction.

The compound (XVI) is prepared by reacting 2-methoxyphenol (XV),

3

Formula XV

with dimethylchloro malonate (XVI), Formula XVI

in the presence of a suitable solvent and a base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide to produce dimethyl-(2- methoxyphenoxy)malonate (XIV).

The solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof. Preferred solvent is the toluene.

The reaction can be performed at a temperature ranging from about 20°C to about 15O⁰C based on the solvents used for the reaction. The compound (XVI) is added to a solution of salt of 2- methoxyphenol (XV) in the organic solvent. Preferably, after removal of water from the solution of compound (XV) by azeotropic distillation.

The sufficient period of time necessary for obtaining compound (XIV) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 1 to about 10 hours. More preferably, the reaction mixture is maintained for about 2 hour to about 3 hours.

Compound (XIV) can be isolated from the reaction mixture by adding a sufficient amount of water to the reaction mixture followed by aqueous base solution to remove unreacted 2-methoxyphenol (XV) followed by removing the solvent to produce an oily mass. Condensing the compound (XIV) with 2-amidinopyrimidinium hydrochloride (II) in the presence of a suitable base in a solvent produces 5-(2-methoxyphenoxy)-2-(pyrimidin-2- yl)tetrahydropyrimidin-4,6-dione (IV).

The base is selected from alkoxide such as sodium ethoxide, sodium isoproxide, sodium tert- butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert- butoxide. The solvent used in the reaction is selected from lower alkanol such as methanol, ethanol, isopropanol or butanol.

The reaction can be performed at a temperature ranging from about -10°C to about 30⁰C based on the solvents used for the reaction. A preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 5 hours. Compound (IV) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, treating with a solvent and crystallizing or precipitating from the reaction medium. Preferably, a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 1 to pH of about 2, more preferably from pH of about 0.5 to pH of about 1.0. Any acid having sufficient pKa to generate the desired pH can be used. Preferably the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid. Preferably, the solvent used is selected from methylene chloride, ethyl acetate, and toluene.

5-(2-Methoxyphenoxy)-2-(pyrimidine-2-yl)-tetrahydropyrimidin-4,6-dione (IV) is reacted with halogenating agent to produce 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va). The halogenating agent is selected from phosphorous oxychloride and phosphorous pentachloride. The reaction can be performed at a temperature ranging from about 20⁰C to about 12O⁰C. A preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 8 hours. After completion of the reaction, the reaction mass was added to a mixture of organic solvent and water and treated with aqueous base. The organic layer was separated and treated with carbon. The resulting filtrate containing 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va) is used as such in the next step, without isolation or the compound (Va) is isolated from the reaction mixture by removing the solvent and crystallizing or precipitation from the solvents.

The solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform. The aqueous base used is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxides, calcium hydroxide.

The reaction of 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va) with 4-(l ,l- dimethylethyl)benzene sulfonamide (VI) in the presence of a suitable base in a solvent produce A-

(1 ,1 -dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide

(Vila).

The suitable base is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures thereof.

The reaction can be performed in the presence of phase transfer catalyst, which is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate. Preferably, tetrabutylammonium bromide.

The reaction is performed at a temperature ranging from about 3O⁰C to about 150⁰C based on the solvents used for the reaction. More preferably, from about 25⁰C to about 120⁰C. A preferred reaction time is from about 1 to about 7 hours, more preferably from about 1 to about 5 hours. Water formed during the reaction is separated by azeotropically. 4-(l ,l-dimethylethyl)-N-[6-halo- 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, extracting with a solvent and removing the solvent and crystallizing or precipitating it from a crystallization solvent. Preferably, a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 0.5 to pH of about 4, more preferably, from pH of about 0.5 to pH of about 1. Any acid having sufficient pKa to generate the desired pH can be used. Preferably the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid. Preferably, the solvent used in the extraction is selected from methylene chloride, ethyl acetate, and toluene. Compound (Vila) can be converted to its salts selected from hydrochloride, hydrobromide.

The reaction of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4- yl]benzenesulfonamide (Vila) or its salt with ethylene glycol to produce Bosentan (I) is carried out in the presence of a base selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures there of and in a solvent.

The solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof. Preferred solvent is toluene.

The reaction can be performed in the presence of phase transfer catalyst, which is a catalyst or agent added to the reaction mixture of components, where it can conveniently and rapidly react with another reacting component. The phase transfer catalyst used is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate. Preferably, tetrabutylammonium bromide.

The reaction can be performed at a temperature ranging from about 15°C to about 130⁰C based on the solvents used for the reaction. More preferably, from about 25°C to about 120⁰C. A preferred reaction time is from about 10 to about 30 hours, more preferably from about 15 to about 24 hours, and most preferably from about 13 to about 24 hours. Preferably from about 10 equivalents to about 130 equivalents of ethylene glycol relative to the 4-(l ,l -dimethylethyl)-N-[6-halo-5-(2- methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonarnide (Vila) is used in the reaction, more preferably from about 50 equivalents to about 120 equivalents.

Bosentan (I) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, extracting with a solvent and removing the solvent and crystallizing or precipitating it from a solvent.

Another embodiment of the present invention relates to the purification of Bosentan of formula I.

Bosentan potassium Form I having X-ray diffraction characteristic peaks at about 5.60 ± 0.2, 6.48 ± 0.2, 9.67 ± 0.2, 10.20 ± 0.2, 1 1.16 ± 0.2, 12.89 ± 0.2, 14.04 ± 0.2, 16.80 ± 0.2, 17.89 ± 0.2, 18.80 ± 0.2, 22.38 ± 0.2 two theta degrees, is prepared by treating crude Bosentan with potassium hydroxide in aqueous alcohol to produce crystalline Bosentan potassium Form I.

The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet- butanol, preferably isopropanol. The salt formation can be carried out at temperature of about 10 to 100⁰C, preferably between 55 to 60⁰C. After cooling to room temperature, the crystalline Bosentan potassium Form I, is isolated by filtration. The crystalline Bosentan potassium Form I obtained by the above process contains less than 0.2 % bis-sulfonamide (VIII) impurity by HPLC.

Bosentan potassium Form II having X-ray diffraction characteristic peaks at about 6.64 ± 0.2, 8.78 ± 0.2, 9.78 ± 0.2, 10.66 ± 0.2, 14.71 ± 0.2, 17.20 ± 0.2, 17.57 ± 0.2, 18.4 ± 0.2, 22.33 ± 0.2, 27.51± 0.2, 29.63 ± 0.2 two theta degrees, is prepared by treating crystalline Bosentan potassium Form I with an acid in a solvent followed by treating with aqueous potassium hydroxide.

The acid used for acidification is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid etc. The solvent used is selected from water. Acidification is carried out at a temperature of about 10 to 100⁰C, preferably between 55 to 60°C. Aqueous potassium hydroxide is added at a temperature of about 10 to 100°C, preferably 55 to 60°C. Crystalline Bosentan potassium Form Il is isolated after cooling the solution to room temperature by filtration and optionally dried. The crystalline Bosentan potassium Form II obtained by the above process contains less than 0.2% of deshydroxy impurity (IX) by HPLC.

Bosentan potassium Form I or Form II is treated with an acid, in a solvent or mixture of solvents to produce Bosentan substantially free from bis-sulfonamide impurity (VIII) and deshydroxy impurity (IX). The acid used is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid etc. The solvent used is selected from water; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride, chloroform; esters such as methyl acetate, ethyl acetate; aromatic hydrocarbons such as toluene, xylene or mixtures thereof. Acid is added to a pH of about 0.5 to 1.0 at temperature of about 0 to 7O⁰C, preferably at about 20 to 5O⁰C. After acidification, the organic layer is separated and removed the solvent to produce the residue. The residue containing Bosentan is dissolved in a solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol, preferably ethanol, at a temperature of about 20 to 100⁰C, preferably 55 to 60⁰C. Treating the resulting solution with carbon enoantichromas and filtered through hyflo bed and the filtrate is heated to reflux temperature and DM water is added at reflux temperature. The resulting reaction mass is cooled to room temperature over a period of 4 to 7 hours to crystallize the Bosentan pure, which is filtered and dried.

It has been observed that the above employed purification process produced substantially pure Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX) by HPLC analysis. Bosentan (I) prepared by the process of the present invention includes its hydrates and solvates.

The present invention also relates to a pharmaceutical composition comprising an effective amount of substantially pure Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX) in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients and the quantity of the compound or composition of the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.

In general, pharmaceutical compositions of the present invention are prepared using conventional materials and techniques,, such as mixing, blending and the like.

According to the present invention, pharmaceutical composition comprising Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX) also include, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, tablets.

The present invention further provides Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX), for use in the manufacture of a medicament for the treatment in hypertension.

The details of the process of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. EXAMPLES:

Example-1

Step-1:

Preparation of dimethyl-(2-methoxyphenoxy)maIonate (XIV)

2-Methoxyphenol (XV) (10Og, 805.54 mmol) was dissolved to toluene (700 ml) at 20-30⁰C and sodium hydroxide (33.83g, 845.75 mmol) was added. The reaction mass was heated to reflux temperature and separated water azeotropically. Thereafter, dimethyl chloromalonate (147.6g, 886.16 mmol) was added at 60-65⁰C over a period of 30 min and heated to reflux temperature and stirred for 3 hrs. The reaction mass was cooled to room temperature, washed with DM water followed by 1% w/v aqueous sodium hydroxide solution and concentrated to yield 195g of the title compound.

Step-2:

Preparation of 2-amidinopyrimidinium hydrochloride (II)

2-Cyanopyrimidine (XIII) (5Og, 475.73 mmol) was added to the solution of sodium ethoxide (3.24g, 47.64 mmol) in methanol (500 ml) at -3 to O⁰C and was stirred for 8 hrs. The reaction mass was allowed to a temperature of 25-3O⁰C and treated with ammonium chloride (26.72g, 499.43 mmol) to yield 2-amidinopyrimidinium hydrochloride (II).

Step-3:

Preparation of 5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-tetrahydropyrimidin-4,6-dione

(IV).

Dimethyl(2-methoxyphenoxy)malonate (XIV) was added to the reaction mass containing 2- aminopyrimidinium hydrochloride (II) prepared in stage-2 at 0-5⁰C. Sodium ethoxide (106.76g, 1570 mmol) was added to the reaction mass at 0-5°C in 1 hrs and maintain at 35°C for 5hrs. Thereafter, the reaction mass was concentrated, dissolved in mixture of DM water (500ml) and toluene (150mi) and acidified to pH 0.5-0.7 with dilute hydrochloric acid at 20-30⁰C. The precipitated product was filtered, washed with toluene followed by water and dried at 75-8O⁰C to yield 129.3g of title compound.

Chromatographic purity. 96.61% (by HPLC, by area normalization) Step-4:

Preparation of 4-(14-dimethylethyl)-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl|benzenesulfonamide (VII).

5-(2-Methoxyphenoxy)-2-(pyrimidin-2-yl)-tetrahydropyrimidin-4,6-dione (IV) (10Og,

320.22mmol) was added to phosphorous oxychloride (196.4g). The resulting reaction mass was slowly heated to 103-105⁰C and stirred for 4 hrs. The reaction mass was added to a mixture of toluene (450ml) and water (350ml) at 20-50⁰C and treated with 30% w/w aqueous sodium hydroxide solution (271.5ml) at 70-80⁰C. The organic layer was separated and treated with activated carbon (7g) at 80-90⁰C for 30min, filtered through hyflo and washed with hot toluene (300ml). 4-(l ,l-Dimethylethyl)benzene sulfonamide (VI) (68.3g, 320.2mmol) was added to the filtrate, followed by potassium carbonate (53.03g, 384.27 mmol) and tetrabutylammonium bromide (3.19g, 9.59 mmol) were added, heated to reflux temperature and separated water azeotropically for 2 hrs, the reaction mass was cooled to 20-25⁰C, filtered the solid and dried. Further, the solid was added to DM water and acidified to pH 0.5 to 0.7 with hydrochloric acid. The solid was filtered washed with DM water and dried to yield 144.5g of title product.

Chromatographic purity: 97.92% (by HPLC, by area normalization)

Step-5:

PREPARATION OF BOSENTAN CRUDE

4-/er/-Butyl-N-[-6-chloro-5-(2-methoxyphenoxy)-[2,2'-bypyrimidin}-4-yl]benzene sulfonamide (VII) (2.8 Kg, 5.32 moles) was added to 5.7% w/v monosodium ethylene glycolate solution (19.6 liters) and the mixture was heated to 1 15°C and maintained for 5 h. The reaction mass was cooled to room temperature and pH was adjusted to 0.5-1.0 with concentrated hydrochloric acid. The product was extracted with methylene chloride, washed with DM water and concentrated to yield Bosentan crude as a pale yellow solid.

Chromatographic purity (By HPLC): 91.75%

Bis-sulfonamide impurity (VIII) (By HPLC): 0.13%

Deshydroxyethyl impurity (IX) (By HPLC): 5.88% Example-2

PREPARATION OF BOSENTAN POTASSIUM FORM I (TO REMOVE DIMER

IMPURITY (VIII))

Bosentan crude obtained in example- l(step-5) was added to the 8% w/w aqueous isopropyl alcohol (28 liter) at room temperature and heated the slurry to 55-60⁰C. Potassium hydroxide (421.5 g, 6.38 moles) was added to the slurry and heated to 75-85°C and maintained for 1 h. Thereafter the reaction mass was cooled to ambient temperature and isolated wet Bosentan potassium (3.9 Kg). Chromatographic purity (By HPLC): 93.58%

Bis-sulfonamide impurity (VIII) (By HPLC): 0.05%

Deshydroxyethyl impurity (IX) (By HPLC): 6.3%

Example-3

PURIFICATION OF BOSENTAN POTASSIUM FORM II (TO REMOVE DESHYDROXY

ETHYL IMPURITY (IX))

Wet Bosentan potassium (3.9 Kg) isolated in Example-2 was added to DM water (14 liter), acidified with concentrated hydrochloric acid (650 g, 6.38 mol) at ambient temperature and the slurry was maintained at 55-60⁰C for 2 h. Potassium hydroxide (526 g, 7.96 mol) was added to the slurry at 55-60⁰C, heated to 90-100⁰C and maintained for 1 h. Thereafter the reaction mass was cooled to ambient temperature and isolated wet Bosentan potassium and dried at 50-60⁰C to yield

2.7 Kg (86%).

Chromatographic purity (By HPLC): 99.72%

Bis-sulfonamide impurity (VIII) (By HPLC): 0.06%

Deshydroxyethyl impurity (IX) (By HPLC): 0.09%

Example-4

PREPARATION OF BOSENTAN MONOHYDRATE

Bosentan potassium (2.7 Kg, 4.23 mol) isolated in Example-3 was added to mixture of DM water (10 liter) and methylene chloride (22.5 liter) and acidified to pH 0.5-1.0 with concentrated hydrochloric acid at 20-30⁰C. The organic layer was separated, washed with DM water and concentrated. The concentrated mass was dissolved in ethanol (6.75 liter) at 60-65°C, treated with carbon enoantichromos (190 g), filtered through hyflo bed and washed with hot ethanol (1.35 liter). The total filtrate was collected, heated to reflux temperature and added DM water (8 liter) at reflux temperature. The resulting reaction mass was allowed to ambient temperature over a period of 6 h to crystallize the product. The product was filtered and dried to yield Bosentan Monohydrate 2.45 Kg (80.8%).

Chromatographic purity (By HPLC): 99.72%

Bis-sulfonamide impurity (VIII) (By HPLC): 0.07%

Deshydroxyethyl impurity (IX) (By HPLC): 0.1 1%

Claims

WE CLAIM

1. Substantially pure Bosentan having less than about 0.2 % of dimer impurity (VIII) and less than about 0.2 % of deshydroxy impurity (IX).

Formula VIII

Formula IX

2. A crystalline Form I of Bosentan potassium.

3. The crystalline Form I of Bosentan potassium as claimed in claim 2, having X-ray diffraction spectrum peaks at about 5.60 ± 0.2, 6.48 ± 0.2, 9.67 ± 0.2, 10.20 ± 0.2, 1 1.16 ± 0.2, 12.89 ± 0.2, 14.04 ± 0.2, 16.80 ± 0.2, 17.89 ± 0.2, 18.80 ± 0.2, 22.38 ± 0.2 two theta degrees.

4. Crystalline Form I of Bosentan potassium as claimed in claim 2, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1.

5. A crystalline Form II of Bosentan potassium.

6. The crystalline Form II of Bosentan potassium as claimed in claim 5, having X-ray diffraction spectrum peaks at about 6.64 ± 0.2, 8.78 ± 0.2, 9.78 ± 0.2, 10.66 ± 0.2, 14.71 ± 0.2, 17.20 ± 0.2, 17.57 ± 0.2, 18.4 ± 0.2, 22.33 ± 0.2, 27.51 ± 0.2, 29.63 ± 0.2 two theta degrees.

7. Crystalline Form II of Bosentan potassium as claimed in claim 5, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2.

8. A process for the preparation of the crystalline Form I of Bosentan potassium, which comprises:

(i) treating crude Bosentan with potassium hydroxide in an aqueous alcohol;

(ii) isolating crystalline Bosentan potassium Form I with less than 0.2 % of bis- sulfonamide impurity (VIII).

9. The process according to claim 8, wherein the alcohol used is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol or mixtures thereof.

10. The process according to claim 8, wherein crystalline Bosentan potassium Form I is isolated by cooling to room temperature, followed by filtration.

1 1. A process for the preparation of the crystalline Form II of Bosentan potassium, which comprises:

(i) acidifying the Bosentan potassium Form I with an acid in a solvent;

(iii) isolating crystalline Bosentan potassium Form II with less than 0.2% of deshydroxy impurity (IX).

12. The process according to claim 1 1 , wherein the acid used in acidification is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic or mixtures thereof.

13. The process according to claim 1 1 , wherein the solvent used in step (i) is water.

14. The process according to claim 1 1, wherein the crystalline Bosentan potassium Form II is isolated by cooling to room temperature, followed by filtration.

15. Substantially pure Bosentan having less then about 0.2% of dimmer impurity (VIII) and less than about 0.2% of deshydroxy impurity (IX), which comprises :

(ii) treating the Bosentan obtained from step(i) using the mixture of water and alcohol;

(iii) isolating the Bosentan.

16. The process according to claim 15, wherein the acid used in step (i) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid or mixtures thereof.

17. The process according to claim 15, wherein the solvent used in step (i) is selected from water; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride, chloroform; esters such as methyl acetate, ethyl acetate; aromatic hydrocarbons such as toluene, xylene or mixtures thereof.

18. The process according to claim 15, wherein the alcohol used in step (ii) is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol or mixtures thereof.

19. The process according to claim 15, wherein the Bosentan is isolated by cooling to room temperature, followed by filtration.

20. The process according to claim 15, wherein the Bosentan is isolated as Bosentan monohydrate.

21. A pharmaceutical composition comprising substantially pure Bosentan having less than about 0.2 % of dimer impurity (VIII) and less than about 0.2 % of deshydroxy impurity (IX).

22. A process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)- [2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its salt,

Formula Vila

Wherein X-represent Cl, Br or I ;

which comprises:

(i) treating 2-cyanopyrimidine (XII), fY^CN Formula XIII

using ammonium chloride in presence of a suitable base in a solvent to produce 2-amidinopyrimidinium hydrochloride of formula II, H₇ HCl Formula II

with the proviso that the base is not sodium methoxide;

(ii) condensing compound of Formula (II) with dimethyl-(2- methoxyphenoxy)malonate (XIV),

Formula XIV

in presence of a suitable base in a solvent to produce 5-(2- methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione (IV),

3 Formula IV

with the proviso that the base is not sodium methoxide;

(iii) treating the compound of Formula (IV) with a halogenating agents to produce 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V),

3 Formula Va

(iv) condensing the compound of Formula (Va) with 4- ( 1 ,1- dimethylethyl)benzene sulfonamide (VI), Formula VI

in presence of a base in a solvent optionally in presence of a phase transfer catalyst to produce compound of formula (Vila) or its salts.

23. The process according to claim 22, wherein the base used in step (i) and step (ii) is selected from alkoxide.

24. The process according to claim 22, wherein the alkoxide is selected from sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isoproxide, potassium tert-butoxide or mixtures thereof.

25. The process according to claim 22, wherein the solvent used in step (i) and step (ii) is selected from lower alkanol such as methanol, ethanol, isopropanol or buatnol or mixtures thereof.

26. The process according to claim 22, wherein the halogenating agents in step (iii) is selected from phosphorous oxychloride or phosphorous pentachloride.

27. The process according to claim 22, wherein the base used in step (iv) is selected from alkali or alkaline earth metal carbonate.

28. The process according to claim 22, wherein the solvent used in step (iv) is selected from aromatic hydrocarbons, halogenated hydrocarbon, polar aprotic solvents or mixtures thereof.

29. The process according to claim 22, wherein the phase transfer catalyst used in step (iv) is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate.

30. A process for the preparation of Bosentan (I) using 4-(l,l-dimethylethyl)-N-[6-halo-5-(2- methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonarnide (Vila) or its salt prepared by the process according to any one of claims 22-29.