The following specification claims priority from Indian Patent Application bearing Number 560/CHE/2009 dated Mar 12, 2009.

FIELD OF THE INVENTION:

The present invention relates to racemization of an undesired optically active 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid, a key intermediate used in the preparation of Ambrisentan. The present invention also relates to a process for the preparation of desired optically active (S)-isomer of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of formula (VI).

The present invention further relates to an improved process for the preparation of Ambrisentan from the compound of formula (VI) and a process for its purification.
The present invention also provides pharmaceutical compositions comprising Ambrisentan and an excipient/carrier, known in the art.

BACKGROUND OF THE INVENTION:

Ambrisentan, chemically known as [(aiS)-a-[(4,6-Dimethyl-2-pyrimidinyl)oxy]-p-methoxy-p-phenylbenzenepropanoicacid] is marketed under the brand name LETAIRIS. It is structurally represented by the compound of formula I and is indicated for the treatment of Pulmonary Arterial Hypertension. (PAH).

Pulmonary Arterial Hypertension (PAH) is an uncommon disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling. It results in increased pulmonary artery pressure and pulmonary vascular resistance and, ultimately, right ventricular heart failure and death.

Ambrisentan is disclosed in US 5,932,730 and US 7,109,205, in which resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid using (S)-l-(4-nitrophenyl)ethylamine in a mixture of acetone and methyltertiarybutylether followed by desaltification of the diastereomeric salt in the presence of concentrated hydrochloric acid to afford (S)-2-hydroxy-3-methoxy-3,3-diphenyIpropionic acid. Further (S)-2-hydroxy-3-niethoxy-3,3-diphenylpropionic acid is reacted with 4,6-dimethyl-2-methyl-sulfonyl-pyriniidine in the presence of a base in dimethylformamide, followed by isolation using column chromatography on silica gel eluting with n-heptane/ethylacetate to give Ambrisentan. Schematic representation of this process is as below in scheme-I.

Prior art process involves column chromatography for isolation of Ambrisentan which is not feasible at industrial level. There remains a need in the art for industrial scale process for purification of Ambrisentan. Accordingly, the present invention involves simple recrystallization method for purification of Ambrisentan which leads to crystalline Ambrisentan having good yield and purity.

OBJECT OF THE INVENTION:
The main object of the present invention is to provide racemization of undesired optically active 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid from a diastereomeric mixture.

Another object of the present invention is to provide, a process for the preparation of desired optically active (S)-isomer of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of formula (VI).

Yet another object of the present invention is to provide an improved process for the preparation of Ambrisentan from compound of formula (VI).

Yet another object of the present invention is to provide a process for the purification of Ambrisentan.

Yet another object of the present invention is to provide crystalline Ambrisentan with improved yield and quality.

Yet another object of the present invention is to provide pharmaceutical compositions comprising Ambrisentan and an excipient/carrier.

BRIEF DESCRIPTION OF THE DRAWINGS:

FIG. 1 is a representative X-ray diffraction pattern of crystalline Ambrisentan

FIG. 2 is a representative X-ray diffraction pattern of crystalline (S)(+)2-hydroxy-3-
methoxy-3,3-diphenyl propionic acid compound of formula-VI.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide a process for racemization of undesired optically active 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid from a diastereomeric mixture which comprises; treating the diastereomeric salt with a base, followed by pH adjustment using an acid and finally isolating racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of formula-IV.

Another aspect of the present invention is to provide an improved process for the preparation of Ambrisentan which comprises: resoluting 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid using a chiral base, optionally purifying the diastereomeric salt, followed by condensing with 4,6-dimethyl-2-methyl-sulfonyl-pyrimidine in the presence of a base in a solvent and isolating Ambrisentan.

Yet another aspect of the present invention is to provide a process for the purification of Ambrisentan which comprises: treating Ambrisentan in a solvent, optionally adding an antisolvent and isolating pure crystalline Ambrisentan.

Yet another aspect of the present invention is to provide pharmaceutical compositions comprising Ambrisentan and an excipient/carrler.

The step wise process for the preparation of Ambrisentan of the present invention is illustrated by the following Scheme-II:

DETAILED DESCRIPTION OF THE INVENTION:

The present invention encompasses an improved process for the preparation of Ambrisentan.

In one embodiment, the present invention encompasses racemization of undesired optically active 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid from a diastereomeric mixture containing R&S isomers of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in the ratio of 90:10 to 10:90, preferably 10-40% of S-isomer.

In another embodiment, the present invention encompasses recycling the unwanted isomer of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid which comprises:

a) adding a base to the diastereomeric sah of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in a solvent,

b) adjusting the pH to 1 -4 with an acid,

c) isolating racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of compound of formula-lV.

According to the present invention, diastereomeric salt of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in aqueous medium is treated with an inorganic base, first organic solvent is added, the reaction mass temperature raised to reflux and maintained at the same temperature for about 8-12 hrs, cooled to 40-60 C and the pH is adjusted to 1-3 using dilute hydrochloric acid and second organic solvent is added. The organic layer is separated and washed with water. The solvent is distilled off completely under vacuum and water is added to the residue. The obtained solid is filtered and washed with water to get racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of compound of formula-IV.

According to the present invention, the inorganic base is selected from aqueous potassium hydroxide or aqueous sodium hydroxide, first organic solvent is selected from methanol or ethanol and second organic solvent is selected from ethers such as methyl tertiary butyl ether.

In another embodiment, the present invention also encompasses an improved process for the preparation of Ambrisentan comprising the steps of:

a) resolving the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of compound of formula-IV using a chiral base in a solvent to give a diastereomeric salt of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid,

b) optionally purifying the salt obtained in step a),

c) treating the diastereomeric salt with an acid to give (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of compound of formula-VI,

d) reacting compound of formula-VI with 4,6-dimethyl-2-methyl-suIfonyl-pyrimidine of compound of formula-VII in the presence of a base in a solvent to give Ambrisentan, and

e) optionally recrystallizing the compound of step d) to get pure Ambrisentan.

According to the present invention, racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic
acid is dissolved in a solvent at reflux temperature. Mixture of triethylamine and a chira!
base are added to the reaction mass and maintained at the reflux temperature for about 30-
70 min. The reaction mass is cooled to 0-5°C and maintained at this temperature for about
2-4 hrs. The obtained solid is filtered, dried at about 30-55°C to give the salt of (R)-(+)-l-
phenylethyl ammonium; (S) (+)2-hydroxy-3-methoxy-3,3-diphenylpropionic acid.

According to the present invention, diastereomeric salt of (R) (+)-l-phenylethyl ammonium; (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionic is optionally purified using a chiral base and further treated with an inorganic acid to get pure (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionic acid, which is reacted with 4,6-dimethyl-2-methyl-sulfonyl-pyrimidine at room temperature in the presence of a base in a solvent, after completion of the reaction water is added, pH is adjusted to 1-3 using aqueous inorganic acid, organic layer is separated and evaporated the solvent to get crude Ambrisentan. The obtained crude Ambrisentan is recrystallized in organic solvent to get pure Ambrisentan.

According to the present invention, solvent used for dissolution of racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid is selected from methanol, ethanol, acetone, butanone, methylethylketone, methyl isobutyl ketone, ethylacetate, tetrahydrofuran, acetonitrile or mixtures thereof and chiral base is selected from (R)-l-phenylethylamine, (S)-1 -phenylethylamine, (R)-N-methyl-1 -phenylethylamine or (S) 1 -(4-
nitrophenyl)ethylamine.

According to the present invention in step d) the base used is selected from sodium hydride, potassium hydride, calcium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, butyllithium, potassium tertiary butoxide, lithium tertiary butoxide, lithium hexamethyldisilazide, lithium diisopropylamide and the solvent is selected from water, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride, trichloroethylene, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane, tetrahydrofriran, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, methanol, ethanol, isopropanol, butanol and ethylene glycol, ethyl acetate, amyl acetate, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or mixtures thereof. The inorganic acid used for pH adjustment is aqueous hydrochloric acid or acetic acid and the solvent used for recrystallization is selected from ethyl acetate, acetone, methanol, ethanol or isopropanol.

In another embodiment, the present invention also encompasses a process for the purification of Ambrisentan comprising the steps of:

a) treating Ambrisentan in a solvent,
b) optionally adding an antisolvent, and
c) isolating pure Ambrisentan.

According to the present invention Ambrisentan is treated with a solvent and temperature of the reaction mass is raised to reflux to get clear solution. Optionally water is added and cooled the reaction mass. The obtained solid is filtered, washed with water and dried at 30-55°C to give pure Ambrisentan.

According to the present invention Ambrisentan is treated with a solvent selected from ketones such as acetone, methylethylketone, methylisobutylketone and the like, alcohols such as methanol, ethanol, isopropanol, esters such as ethylacetate, methylacetate, ethers such as tetrahydrofuran, dioxane. Reaction mass temperature is raised to reflux. Carbon treatment is given, filtered and washed with the solvent. An antisolvent selected from water is added to the solution and temperature of the reaction mass was raised to reflux.

The reaction mass is cooled, filtered, washed with water and dried at 30-55°C to give pure Ambrisentan.

According to the present invention the term "treating" herein refers to dissolving, contacting, suspending or slurrying in a solvent.

Yet another embodiment, the present invention encompasses crystalline Ambrisentan characterized by X-ray diffraction pattern with peaks at 8.83, 12.25, 13.03, 14.08, 14.78, 15.13, 15.49, 16.65, 17.77, 18.19, 18.82, 20.50, 21.90, 22.83, 24.19, 25.15, 25.53, 26.81, 27.53, 28.83, 34.60, 36.58, 40.37, 42.94 and 45.98 ± 0.20 as shown in fig 1.

In another embodiment, the present invention also encompasses Ambrisentan having HPLC purity more than 99.0%, preferably more than 99.5%.

In another embodiment, the present invention also encompasses Ambrisentan having Chiral purity more than 99.0%, preferably more than 99.5%.

In yet another embodiment, the present invention also encompasses Ambrisentan having the particle size distribution of d90 less than 50fxm, preferably d90 less than 20^m.

In another embodiment, the present invention encompasses crystalline (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionic acid of formula-VI characterized by X-ray diffraction pattern with peaks at 10.78, 11.71, 14.42, 16.00, 16.62, 17.26, 18.83, 20.45, 20.99, 21.75, 23.06, 23.60, 24.02, 25,21, 27.40, 28.26, 29,11, 32.39, 34.82 and 38.29 ± 0,28 as shown in
fig 2.

The present invention also provides pharmaceutical compositions comprising Ambrisentan and an excipient/carrier.

The term "pharmaceutical compositions" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferred dosage forms are tablets.

The excipients included in the composition are those which are customary and known to a person skilled in the art. These include without any limitations, diluteuents, fillers, binders, disintegrants, surfactants, stabilizers, glidants, lubricants etc.

The tablets can be prepared by conventional processes known to a person skilled in the art. Preferably, processes employed for the preparation of the tablets according to the invention include both dry granulation and direct compression.

Advantages of the present invention:

a) Recycling of (-) 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid the unwanted isomer to its racemic form, there by converting to specific enantiomer resulting increase in the yield of the product.

b) Purification of Ambrisentan by using simple recrystallization technique to get pure compound,

The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in any way.

EXAMPLE-1: 2-hydroxy-3-inethoxy-3,3-diphenyl-propionic acid.
Benzophenone (200g) was dissolved in methyl tertiary butyl ether (700ml) followed by the addition of sodium methoxide (lOlg) and cooled to 0-5°C. Methylchloroacetate in methyl teriary butyl ether (210g in 200ml) was slowly added to the reaction mixture for about 4-5 hrs and stirred for about 1.2 hrs. Water (800ml) was added to the reaction mixture, separated the organic layer and washed the organic layer with water (500ml). Distilled off the solvent completely under vacuum. Methanol (550 ml) was added to the residue thus obtained after distillation. Boron trifluoride etherate (3ml) was added to the reaction mass for about 15-30 min and stirred for about 2-3 hrs. Distilled off the methanol at atm pressure to a minimum volume, cooled the reaction mass to 0-5°C and maintained at the same temperature for about 30 min. Filtered the solid and washed with methanol (50ml). To the wet material thus obtained was added 10% sodium hydroxide solution (880ml) and heated to reflux followed by distillation. Cooled the reaction mass to 60^C and water (200ml) was added. Adjusted the pH of the reaction mass to 2 with dilute hydrochloric acid (70ml). Cooled the reaction mass to 25-35°C and stirred for about 3 hrs. Filtered the solid and washed with water (200ml). Dried the wet compound at 50-55T to get 220-280 g of title compound.

EXAMPLE-2: (S) (+) 2- hydroxy-3-methoxy-3,3-diphenylpropionic acid.
(±) 2- Hydroxy-3-methoxy-3,3-diphenylpropionic acid (50g, 0.183 mole) was added to acetone (2500ml). Stirred the reaction mass for 10 min at 25-35°C and raised the temperature to 55-57°C. Triethylamine (9.2g, 0.0091 mole), R (+)-l-phenyl ethyl amine (12g, 0.0099 mole) were added to the reaction mass and maintained at 55~5TC for 45-60 min. Slowly cooled the mass to 25-35°C and further cooled to 0-5°C. The reaction mass was maintained at 0-5°C for about 3 hrs. Filtered the solid, washed with acetone (25ml) and dried at 40-45°C to give 21g of salt of (R)(+)-l-PhenylethyI ammonium;(S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionate. Water (200ml) was added to salt thus obtained, pH adjusted to <2 with dilute hydrochloric acid and stirred the mass for 120 min at 25-35°C. Solid was filtered, washed with water (20ml) and dried at 40-45°C to give 12.8g of (S)(+) 2- hydroxy-3-methoxy-3,3-diphenylpropionic acid. Chiral HPLC> 93%. This material was added to a mixture of isopropyl alcohol (256ml) and acetone (333ml). Stirred the mass for 10 min at 25-35°C and raised the temperature to 60-63°C. R (+)-l-Phenyl ethylamine (5.7g, 0.047 moles) was added. The reaction mass was maintained at 60-63°C for 45-60 min. Slowly cooled the reaction mass to 25-35°C and further cooled to 0-5'*C. The reaction mass was maintained at 0-5°C for 2 hrs. Solid was filtered and washed with acetone (6.4ml), dried at 40-45*'C to give 14.3g of pure diastereomeric sah of (R)(+)-1-phenylethyl ammonium (S) (+) 2- hydroxy-3-methoxy-3,3-diphenylpropionate. This salt was added to water (143ml), adjusted pH to <2 with dilute hydrochloric acid and stirred the mass for 120 min at 25-3 5''C. Filtered the solid and wash with water(20ml), dried at 40-45°C to give 9.3g of (S) (+) 2- hydroxy-3-methoxy-3,3-diphenylpropionic acid characterized by PXRD with peaks at 10.79, 11.71, 14.43, 16.00, 16.63, 17.27, 18.83, 20.45, 21.00, 21.75, 23.06, 23.61, 24.03, 25.22, 27.41, 28.27, 29.12, 32.40, 34.82 and 38.30 ±0.20 shown in Fig.2. Chiral HPLO 99.8%.

EXAMPLE 3: Direct isolation of pure (S) (+)2-Hydroxy-3-methoxy-3,3-diphenyl propionic acid.
(±) 2- Hydroxy-3-methoxy-3,3-diphenyl propionic acid (50g 0.183 mole) was added to acetone (1750 ml), stirred the reaction mass for about 10 min at 25-35°C. R(+)-l-Phenylethyl amine (12g 0.0099 mole) , triethylamine (9.2g 0.0091 mole) were added to the reaction mass and maintained for 60 min at 25-35°C. Slowly cooled the mass to 0-5°C.

The reaction mass was maintained at 0-5°C for about 3 hrs. Filtered the solid and dried at 40-45°C to give 20g of salt of R(+)-l- phenylethyl ammonium (S)(+)2-Hydroxy-3-methoxy-3,3-diphenyl propionate. Chiral HPLC > 90 %.

This material was added to a mixture of isopropyl alcohol (260 ml) and acetone (340 ml) Stirred the mass for about 10 min at 25-35°C, raised the temperature to 60-63°C and maintained the reaction mass for 30 min at reflux temperature. Slowly cooled the mass to 25-35°C and further cooled to 0-5°C. The reaction mass was maintained at 0-5*^0 for about 3 hrs. Filtered the solid, washed with mixture of acetone (10 ml), isopropyl alcohol (10ml) , to give 16g of pure diastereomeric salt of R(+)-l- Phenylethyl ammonium (S)(+)2-Hydroxy-3-methoxy -3,3-diphenyl propionate. This salt was added to water (200 ml) adjusted the pH to <2 with dilute hydrochloric acid and stirred the mass for 120min at 25-35°C, Filtered the solid and washed with water and dried at 40-45°C to give 9.0g of pure (S)(+)2-Hydroxy-3-methoxy -3,3-diphenyl propionic acid.

EXAMPLE-4: (R)(+)-l-phenylethylammonium;(S)(+)2-hydroxy-3-methoxy-3,3-
diphenyl propionate diastereomeric salt.
(±) 2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (5g, 0.0183 mole) was added to a mixture of isopropyl alcohol (100ml) and acetone (130ml). Stirred the reaction mass for 10 min at 25-35''C and raised the temperature 60-65°C. Triethylamine (0.92g, 0.0091 mole), R (+)-l-Phenyl ethylamine (1.2g, 0.0099 mole) were added to the reaction mass and maintained at 60-65°C for 30-45mins. Slowly cooled the mass to 25-35°C and further cooled to 0-5°C. Seeding material (O.lg) of (S) (+) 2- Hydroxy-3-methoxy-3,3-diphenylpropionic Acid (R) (+)-l-Phenylethyl amine salt was added. Maintained the reaction mass at 0-5°C for 1 hr. Filtered the solid and washed with mixture of isopropyl alcohol and acetone (5ml), dried at 40-45°C to give 1.6g (0.00407 mole ) 44.29% of theory( based on racemate) of pure diastereomeric salt of (R) (+)-l-Phenylethyl ammonium (S) (+) 2- Hydroxy-3-methoxy-3,3-diphenylpropionate. Chiral HPLC> 99.2%.

EXAMPLE-5:(S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3^-diphenyl propanionic acid.
(S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropiomc acid (30g, 0.11 mole) and lithium tertiary butoxide (18.5g, 0.23 mole) were added to THF (210ml) at 25-30°C. Stirred the reaction mass for 10 min at 25-35°C. To this reaction mixture 4,6-dimethyl-2-metiiyl suifonyl pyrimidine (20.5g, 0.11 mole) in THF(120ml) was added slowly for about 8-10 hrs at 25-30°C. The reaction mass was maintained at 25-30°C for about 10-12 hrs. water (100ml) and ethylacetate (100ml) was added to reaction mass and pH adjusted to <2 with dilute hydrochloric acid at 25-30°C. The reaction mass was stirred for 30 min at 25-35°C. The layers were separated and organic layer was washed with saturated sodium chloride solution. Distilled off the solvent completely under vacuum below 50°C. Ethylacetate (60ml) was added to the residue and stirred the mass for 60 min at 25-35°C. Filtered the solid, washed with ethylacetate (30ml) and dried at 40-45°C to give 34g of (S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropionic acid characterized by PXRD with peaks at 7.98, 8.86, 12.27, 13.05, 14.12, 14.80, 15.15, 15.52, 16.69, 17.78, 18.26, 18.84, 19.44, 19.85, 20.53, 21.93, 22.84, 24.23, 25.15, 26.45, 26.81, 27.54, 28.85, 29.35, 29.90, 31.04, 32.81, 32.77, 34.63, 36.54, 38.39, 40.37, 42.97, 45.99, 46.98, 25.56, 22.49, 32.01 and 41.87 ± 0.29 shown in Fig.l. Chiral HPLO 99.8%; Purity by HPLC > 97%.

Example-6: Recovery of (±) 2-Hydroxy-3-methoxy-3,3-diphenyl-propionic acid by recycling R-isomer of 2-Hydroxy-3-niethoxy-3,3-dipheny!-propionic acid using Potassium hydroxide.
2- Hydroxy-3-methoxy-3,3-diphenylpropionic acid (50g) (isolated from ML's of Example 2 and Example-3 by distillation of solvent and acidification of the residue with diluteute aq hydrochloric acid) (containing 30-40% of S-isomer) was added to 30% potassium hydroxide solution (100 ml). Stirred the reaction mass for about 10 min at 25-35°C. Methanol (5ml) was added and raised the temperature to 100-110°C. The reaction mass was maintained at 100-110°C for about 10-12 hrs. Slowly cooled the reaction mass to 50-55°C, adjusted pH to 2 with dilute hydrochloric acid (65ml). methyltertiarybutylether (MTBE) (100 ml) was added. Stirred the mass for about 30min. Separated the organic layer and washed with water (50ml). Distilled off the solvent completely at 50 -55*'C under vacuum. Water (100 ml) was added and stirred for 60 min. Filtered the solid and washed with water (20 ml), dried at 40-45°C to give 48g of 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid. Chiral HPLC- 50%.

EXAMPLE-7: Purification of (S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenyl propanionic acid.

(S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropionicacid (32g) was added to acetone (320ml) at 25-30''C and raised the temperature to 55-58°C. Carbon (1.6g) was added and maintained the reaction mass at 55-58°C for 30 min. Filtered and washed with acetone (16ml) at 55°C. Water (480ml) was added to the acetone layer at 55-60°C. Stirred the reaction mass for 30-45 min at 55-60°C. Slowly cooled the reaction mass to 25-35'*C and maintained for about 60 min. Solid is filtered, washed with water (32ml) and dried at 40-45°C to give 27.7g of pure (S)(+)2-(4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-diphenylpropionic acid characterized by PXRD with peaks at 8.83, 12.25, 13.03, 14.09, 14.79, 15.14, 15.50, 16.66, 17.77, 18.20, 18.83, 20.50, 21.91, 22.84, 24.19, 25.16, 25.53, 26.81, 27.53, 28.84, 34.60, 36.59, 40.37, 42.94 and 45.98 ± 0.26. Chiral HPLO 99.8%; HPLC (RS) > 99.8%

EXAMPLE-8: Purification of (S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenyl propionic acid.
(S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropionic acid (0.5g.) was added to methanol (5ml) at 25-30^C and raised the temperature to 60-65°C. Carbon was added to the reaction mass and maintained at 60-65°C for 30 min. Filtered the solid and washed with methanol at 60°C. Water (10ml) was added to methanol layer at 60-65°C and stirred the mass for 30-45 min at 60-65°C. Slowly cooled the mass to 25-35°C and stirred the mass for 60 min at 25-35°C. Solid was filtered, washed with water (5ml) and dried at 40-45°C to give 0.35g of pure (S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3 -diphenylpropionic acid. Chiral HPLO 99.9%; HPLC (RS) > 99.0%.
EXAMPLE-9: Purification of (S)(+)2-(4,6-dimetIiyIpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenyl propionic acid.

(S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropionic acid (0.4g) was added to ethanol (3ml) at 25-30°C and raised the temperature to 65-70°C. Carbon was added to the reaction mass was maintained at 65-70°C for 30 min. Filtered the solid and washed with ethanol at 65°C. Water (6ml) was added to ethanol layer at 65-70°C. Stirred the mass for 30-45 min at 65-70°C. Slowly cooled the mass to 25-35°C and stirred the mass for about 60 min at 25-35°C. Solid is filtered, washed with water (3ml) and dried at 40-45ºC to give 0.3g of (S)(+)2-(4,6-dimethylpyrimidin-2-yI)oxy-3-methoxy-3,3-diphenylpropionic acid. Chiral HPLC> 99.9%; HPLC (RS) > 99.5%.

EXAMPLE-10: Purification of (S)(+)2-(4,6-dimethylpyriiiiidiii-2-yI)oxy-3-methoxy-3,3-diphenyl propionic acid.
(S)(+)2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropionic acid (2g) was added to ethyl acetate (30ml) at 25-30°C and raised the temperature to 75-80''C. Carbon was added to the reaction mass and maintained at 75-80°C for 30 min. Filtered the solid and washed with ethyl acetate at 75°C. Slowly cooled the mass to 25-35°C, further cooled to 0-5^C and maintained the mass at 0-5°C for 2 hrs. Solid was filtered, washed with ethyl acetate (1ml) and dried at 40-45°C to give 1.6g of (S)(+)2-(4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-diphenylpropionicacid. Chiral HPLO 99.9%; HPLC (RS) > 99.5%.

EXAMPLE-11: Purification of (S)(+)-2(4,6-DimethyI-pyrimidin-2-yl)oxy-3-methoxy-33-diphenyl-propionic acid.
(S)-2-(4,6-Dimethyl-pyrimidin-2-yi)oxy-3-methoxy-3,3-diphenyl-propionic acid (lOOg) was added to isopropyl alcohol (1500 ml) at 25-30°C and raised the temperature to 60-65°C , BW carbon ( 5g) was added and maintained for 30 min at 60-65°C. Filtered and washed with isopropyl alcohol (100 ml) at 50-55°C. Water (2500 ml) was added to the isopropyl alcohol layer at 50-55°C for 60 min, the reaction mass was cooled to 25-35°C and maintained for about 120 min. Filtered the solid and washed with water(100 ml) and dried at 40-45°C to give 85 g of Pure (S)(+)2-(4,6-Dimethyl-pyrimidin-2-yl)oxy-3-methoxy-3,3-diphenyl-propionic acid. Purity by HPLC 99.80%.

EXAMPLE-12: Brief manufacturing process for the pharmaceutical compositions comprising Ambrisentan so prepared and an excipient/carrier is given below.

Unit Composition:

a. Direct compression:

1. Sift Ambrisentan, Microcrystalline cellulose, lactose monohydrate Croscarmellose sodium and blend in blender
2. Sift Magnesium stearate and blend adding to Step 1
3. Compress the step 2 blend to tablets
4. Coat the core tablets using OpadryTM.

b. Roller compaction:
1. Compact Ambrisentan, Microcrystalline cellulose, lactose and Croscarmellose sodium using Roller compactor.
2. Mill the compacts using screen to get granules.
3. Sift microcrystalline cellulose and Croscarmellose sodium blend along with Step 2 granules.
4. Sift Magnesium stearate and blend adding to Step 3.
5. Compress the step 4 blend to tablets.
6. Coat the core tablets using Opadry .

We Claim:
1. A process for the preparation of (±)-2-hydroxy-3-metlioxy-3,3-diphenylpropionic acid from diastereomeric mixture, comprising the steps of:

a) adding a base to diastereomeric mixture of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in a solvent,

b) adjusting the pH to 1 -4 with an acid, and

c) isolating racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid.

2. The process according to claim 1, wherein the diastereomeric mixture contains, R&S isomers of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in the ratio of 90:10 to 10:90.

3. The process according to claim 1, wherein the base in step a) is selected from aqueous potassium hydroxide or aqueous sodium hydroxide and the solvent is selected from methanol, ethanol or isopropanol.

4. An improved process for the preparation of Ambrisentan, which comprises the steps of:

a) resolving the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropiomc acid as prepared according to claim 1, using a chiral base in a solvent to give a diastereomeric sah of 2-hydroxy-3-methoxy-3,3-diphenylpropiomc acid,
b) optionally purifying the salt obtained in step a),
c) treating the diastereomeric salt with an acid to give (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropiomcacid,
d) reacting (S)(+)2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with 4,6-dimethyl-2-methyl-sulfonyl-pyrimidine in the presence of a base in a solvent, and
e) optionally recrystallizing the compound obtained in step d) to get pure Ambrisentan.

5. The process according to claim 4, wherein the chiral base in step a) is selected from
(R)-1 -phenylethylamine, (S)-1 -phenylethylamine, (R)-N-methyl-1 -phenylethylamine
or (S)l-(4-nitrophenyl)ethylamine and the solvent is selected from methanol, ethanol, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, tetrahydrofuran, acetonitrile, water or mixtures thereof.

6. The process according to claim 4, wherein the purification of the diastereomeric salt in step b) is carried out in the presence of a chiral base selected from (R)-l-phenylethylamine, (S)-1 -phenylethylamine, (R)-N-methyl-1 -phenylethylamine and (S)l-(4-nitrophenyl)ethylamine and the solvent is selected from methanol, ethanol, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, tetrahydrofuran, acetonitrile or mixtures thereof

7. The process according to claim 4, wherein the acid used in step c) is aqueous hydrochloric acid.

8. The process according to claim 4, wherein the base in step d) is selected from sodium carbonate, potassium carbonate, butyllithium, potassium tertiary butoxide, lithium tertiary butoxide or lithium hexamethyldisilazide and the solvent is selected from solvents water, acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone or mixtures thereof.

9. A process for the purification of Ambrisentan, which comprises the steps of:

a) treating Ambrisentan in a solvent,
b) optionally adding an antisolvent, and
c) isolating pure crystalline Ambrisentan.

10. The process according to claim 9, wherein the solvent is selected from acetone, methylethylketone, methylisobutylketone, methanol, ethanol, isopropanol, ethylacetate, methylacetate, tetrahydrofiiran or dioxane and the antisolvent is water.

11. Ambrisentan prepared according to claim 4, having HPLC purity more than 99.0% and chiral purity more than 99.0%.

12. Ambrisentan prepared according to claim 4, having the particle size distribution of d90 less than 30μm.

13. A pharmaceutical composition comprising Ambrisentan prepared according to claim 4, and a pharmaceutically acceptable excipient/carrier.