PRIORITY

This patent application claims the benefit under Indian provisional application IN 2132/CHE/2010 filed on July 28, 2010, entitled "AN IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN" and an Indian provisional application 1104/CHE/2011 filed on April 01, 2011 and entitled "AN IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN", the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Bosentan of 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 ETB. Endothelin (ET-1) is a neurohormone, the effects of which are mediated by binding of ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role of ET-1. Bosentan has a slightly higher affinity for ETA 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 (la), 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-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrirnidine (V). Condensation of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V) with 4-(l,l-dimethylethyl)benzenesulfonamide (VI) in the presence of dimethylsulfoxide to 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 (la).

The process is as shown in Scheme -I below:

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.

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 (XII), which is further treated with base to produce Bosentan (I).

The process is as shown in Scheme -II below:

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 (VII) and isolating Bosentan (I).

The process is as shown in Scheme -III below:

Scheme III

When we carry 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 throughput. Additionally, repeated crystallizations reduce the yield as some Bosentan remains un-crystallized and is not recovered from the liquid phase.

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 0.1% by HPLC analysis.

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 effective process for the preparation of Bosentan using the above crystalline Bosentan potassium Form I and Form II.

SUMMARY OF THE INVENTION

The present invention provides a crystalline Bosentan potassium Form I, characterized by X-ray diffraction spectrum of 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, 11.16 ± 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 of 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 0.1 % of bis-sulfonamide (VIII) impurity.

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).

Another embodiment of the present invention provides a process for the preparation of crystalline Bosentan potassium Form II, which comprises:

(i) treating the Bosentan potassium Form I with alkali metal sulfate or 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 0.1% of deshydroxy impurity (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) treating the crystalline Bosentan Potassium Form I or Form II with alkali metal sulfate or 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.

BRIEF DESCRIPTION OF THE DRAWINGS

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

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 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, 11.16 ± 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, tert-butanol, preferably isopropanol. The salt formation is carried out at temperature of about 10 to 100°C, preferably between 55 to 60°C. After cooling to room temperature, the crystalline Bosentan potassium Form I is isolated by filtration. The crystalline Bosentan potassium Form I is obtained by the above process contains less than 0.1 % 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 alkali metal sulfate or an acid in a solvent followed by treating with aqueous potassium hydroxide.

The alkali metal sulfate used is selected from sodium hydrogen sulfate, sodium metabisulfite, sodium hydrosulfite, potassium hydrogen sulfate, potassium metabisulfite, potassium hydrosulfite or mixture thereof. 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. The reaction is carried out at a temperature of about 10 to 100°C, 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 II 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 0.1% of deshydroxy impurity (IX) by HPLC.

Bosentan potassium Form II is treated with Alkali metal sulfate or an acid, in a solvent or mixture of solvents to produce Bosentan substantially free from bis-sulfonamide impurity (VIII) and deshydroxy impurity (IX). Alkali metal sulfate is selected from sodium hydrogen sulfate, sodium metabisulfite, sodium hydrosulfite, potassium hydrogen sulfate, potassium metabisulfite, potassium hydrosulfite or an 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 70°C, preferably at about 20 to 50°C. 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, tert-butanol, preferably ethanol, at a temperature of about 20 to 100°C, preferably 55 to 60°C.

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 monohydrate 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 crude used in the present invention may be prepared by the process disclosed in US 5,292,740.

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, suoh 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 following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

Example

Step-A:

PREPARATION OF BOSENTAN CRUDE

4-tert-Butyl-N-[-6-chloro-5-(2-methoxyphenoxy)-[2,2'-bypyrimidin}-4-yl]benzene sulfonamide (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 115°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%

Step-B:

PREPARATION OF BOSENTAN POTASSIUM FORM I (TO REMOVE DIMER IMPURITY (VIII))

Bosentan crude obtained in step-a was added to the 8% w/w aqueous isopropyl alcohol (28 liter) at room temperature and heated the slurry to 55-60°C. 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%

Step-C:

Method-I:

PURIFICATION OF BOSENTAN POTASSIUM FORM II (TO REMOVE DESHYDROXY ETHYL IMPURITY (IX))

Wet Bosentan potassium (3.9 Kg) isolated in step-B 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 55-60°C for 2 h. Potassium hydroxide (526 g, 7.96 mol) was added to the slurry at 55-60°C, heated to 90-100°C and maintained for 1 h. Thereafter the reaction mass was cooled to ambient temperature and isolated wet Bosentan potassium and dried at 50-60°C 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%

Method-II:

i) PURIFICATION OF BOSENTAN POTASSIUM FORM II IN WATER (TO REMOVE DESHYDROXY ETHYL IMPURITY (IX))

Wet Bosentan potassium (27.95 Kg) isolated in Step-B was added to DM water (55 liters), treated with sodium hydrogen sulfate monohydrate (4.35 Kg) dissolved in DM water (11 liter) at ambient temperature and the slurry was maintained at 55-60°C for 2 h. Potassium hydroxide (2.60 Kg, 39.46 mol) was added to the slurry at 55-60°C, heated to 90-100°C and maintained for 1 h. Thereafter the reaction mass was cooled to ambient temperature and isolated wet Bosentan potassium to yield 17.35 Kg.

Chromatographic purity (By HPLC): 98.75%
Bis-sulfonamide impurity (VIII) (By HPLC): 0.06%
Deshydroxyethyl impurity (IX) (By HPLC): 1.05%

ii) PURIFICATION OF BOSENTAN POTASSIUM FORM II (TO REMOVE DESHYDROXY ETHYL IMPURITY)

Bosentan potassium Form II (17.35 Kg ) obtained from Method II was added to mixture of DM water (55 liters) and methylene chloride (125 liters) and acidified to pH 1.0-2.0 with sodium hydrogen sulfate monohydrate (4.97 Kg) dissolved in DM water (13.8 liters) at 20-30°C. The organic layer was separated, washed with DM water and concentrated. The concentrated mass was dissolved in potassium hydroxide (2.60 Kg, 39.46 mol) at 55-60°C and maintained for lh, Thereafter the reaction mass was cooled to ambient temperature and filtered and dried at 50-60°C to yield Bosentan potassium 10.38 Kg.

Chromatographic purity (By HPLC): 99.80% Bis-sulfonamide impurity (VIII) (By HPLC): 0.06% Deshydroxyethyl impurity (IX) (By HPLC): 0.06%

Step-D:

PREPARATION OF BOSENTAN MONOHYDRATE

Bosentan potassium (10.8 Kg, 18.33 mol) isolated in Step-C was added to mixture of DM water (60 liters) and methylene chloride (84 liters) and acidified to pH 1.0-2.0 with sodium hydrogen sulfate monohydrate (3.51 Kg) dissolved in water (10.8 liters) at 20-30°C. The organic layer was separated, washed with DM water and concentrated, which is dissolved in ethanol (27 liters) at 60-65°C, treated with carbon enoantichromos (760 g), filtered through hyflo bed and washed with hot ethanol (5.4 liters). The total filtrate was collected, heated to reflux temperature and added DM water (32.4 liters) 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 9.98 Kg.

Chromatographic purity (By HPLC): 99.83% Bis-sulfonamide impurity (VIII) (By HPLC): 0.04% Deshydroxyethyl impurity (IX) (By HPLC): 0.04%

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).

2. A crystalline Form I of Bosentan potassium having X-ray diffraction spectrum peaks at about 5.60 ± 0.2, 6.48 ± 0.2, 9.67 ± 0.2, 10.20 ± 0.2, 11.16 ± 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 substantially as shown in Figure 1.

3. A crystalline Form II of Bosentan potassium 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 substantially as shown in Figure 2.

4. 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).

5. The process according to claim 4, wherein the alcohol used in step (i) is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tert-butanol or mixtures thereof and crystalline Bosentan potassium Form I is isolated in step (ii) by cooling to room temperature, followed by filtration.

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

(i) treating the Bosentan potassium Form I with an alkali metal sulfate or an acid
in a solvent; (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).

7. The process according to claim 6, wherein the alkali metal sulfate used in step (i) is selected from sodium hydrogen sulfate, sodium metabisulfite, sodium hydrosulfite, potassium hydrogen sulfate, potassium metabisulfite, potassium hydrosulfite and the acid used in step (i) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic or mixtures thereof and the solvent used in step (i) is water and the crystalline Bosentan potassium Form II' is isolated by cooling to room temperature, followed by filtration.

8. 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 I or Form II with an alkali metal sulfate or 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.

9. The process according to claim 8, wherein the alkali metal sulfate used in step (i) is selected from sodium hydrogen sulfate, sodium metabisulfite, sodium hydrosulfite, potassium hydrogen sulfate, potassium metabisulfite, potassium hydrosulfite and the acid used in step (i) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid or mixtures thereof and 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 and the alcohol used in step (ii) is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol or mixtures thereof and the Bosentan is isolated by cooling to room temperature, followed by filtration and the Bosentan is isolated as Bosentan monohydrate.

10. 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).