Improved Process for the Preparation of Ambrisentan
Field of the Invention:
The present invention relates to an improved process for the preparation of ambrisentan as well as its intermediate compounds. Ambrisentan is chemically known as (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoicacid, which is represented by the following formula-1.

Formula-1 Ambrisentan is a vasodilator drug that has been developed by Myogen for the treatment of pulmonary arterial hypertension (PAH). Ambrisentan is one of several newly developed vasodilator drugs that specifically target the ETA receptors, inhibiting their action and preventing vasoconstriction. Ambrisentan is marketed under the brand name LETAIRIS, which is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.
Background of the Invention:
Ambrisentan and its pharmaceutically acceptable salts are disclosed in US 5932730. The disclosed process comprises of reacting benzophenone with methyl chloroacetate in presence of sodium methoxide in tetrahydrofuran providing 3,3-diphenyl oxirane-2-carboxylic acid methyl ester, which on in-situ treatment with methanol and BF3/Et20 in diethyl ether provides 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester. Thus obtained methyl ester is hydrolyzed and then resolved with L-proline methyl ester to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. The conversion of this ester intermediate into ambrisentan has not been disclosed. Instead the patent disclosed the preparation of an analogue of ambrisentan involving the reaction of

2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methyl sulfonyl-3,3-diphenylpropionic [sic] acid with glacial acetic acid and hydrogen peroxide.
The drugs of future 2005, 30(8), 765-770 disclosed the preparation of racemic ambrisentan involving the condensation of benzophenone with methyl 2-chloroacetate in presence of sodium methoxide in THF, which gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester, which on subsequent treatment with BF3/Et20 and methanol yields 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester. Thus obtained methyl ester compound on condensation with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine in presence of potassium carbonate in DMF provides the condensed ester compound, which on hydrolysis with potassium hydroxide in dioxane provides ambrisentan. The racemic ambrisentan obtained is converted into active compound by resolving with chiral amine. But the experimental details are not disclosed for the same.
An article published in 'Research Disclosure' disclosed a process for the preparation of ambrisentan. The process comprises of the condensation of (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid and 4,6-dimethyl-2-(methylsulfonyl)pyrimidine in presence of lithium amide in dimethyl formamide, followed by extraction of the reaction mixture with tertiary butyl ether. The ether layer is concentrated and petroleum ether is added to the concentrate to provide ambrisentan. This article does not disclose any physical characteristics of ambrisentan. Other than this article there is no other document which discloses a process for the preparation of ambrisentan except the hydrolysis step.
Moreover the reported processes of ambrisentan and its intermediates involve the usage of ether solvents for final isolation, which is commercially not recommendable.
Organic Process Research & Development 2001, 5,16-22 and J.Med.Chem, 1999, 41, 3026-3032 disclosed a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester a key intermediate in the synthesis of ambrisentan. It involves esterification of its acid which is of high purity using sodium methoxide/potassium carbonate and dimethyl sulphate in dimethyl formamide to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as a crude oil. When a number of reactions were conducted using high pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid, we were able to get as maximum of 60% purity of methyl ester

compound as an oil irrespective of the purity of starting acid compound. Hence it is difficult to purify the ester intermediate compound in an oil form and when we use the same for the preparation of ambrisentan it leads to the product with high levels of impurity.
Hence a focus of the invention was to prepare (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester of high purity so that it could be used to prepare ambrisentan with substantially high yields and also in a quality which could meet the specifications set by of ICH.
(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester has been reported as an oil. In the present invention it was isolated as a crystalline solid which not only improved the yields but also its quality. This when used in the subsequent stages provided ambrisentan in high yields and of high purity.
Polymorphism is the formation of a variety of crystalline forms of the same compound having distinct crystal structures and physical properties like melting points, X-ray diffraction pattern, infrared absorption pattern in fingerprint region, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The difference in the physical properties of different crystalline forms results in some forms having distinct advantageous physical properties compared to other crystalline forms of the same compound. The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the art can understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important qualities like chemical quality, particle size, and polymorphic content. There is a need in the art for the preparation of new polymorphic form of ambrisentan and its pharmaceutically acceptable salts.
The aim of the present invention is to overcome the drawbacks of prior art and to provide an improved process for the preparation of high pure ambrisentan and (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as well as their crystalline forms.

Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of ambrisentan compound of formula-1, which comprises of the following steps:
a) reacting the benzophenone, compound of formula-2 with alkyl chloroacetate compound of formula-3 in presence of a suitable base in a suitable solvent to provide 3,3-diphenyloxirane-2-carboxylic acid alkyl ester, which is reacted in-situ with methanol in presence of a suitable acid to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-5,
b) hydrolyzing the alkyl ester compound of formula-5 with a suitable base in a suitable solvent to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6,
c) resolving the acid compound of formula-6 with a suitable resolving agent in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound offormula-7,
d) reacting the compound of formula-7 with suitable alcohol in presence of a suitable acid catalyst followed by isolation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-8 in a suitable hydrocarbon solvents,
e) purifying the alkyl ester compound of formula-8 using suitable alcoholic solvents,
f) reacting the alkyl ester compound of formula-8 with 4,6-dimethyl-2-(methylsulphonyl)pyrimidine compound of formula-9 in presence of a suitable base in a suitable solvent and isolating the ester compound of formula-10 by addition of water,
g) hydrolyzing the ester compound of formula-10 in presence of a suitable aqueous base in a suitable solvent followed by isolation of ambrisentan compound of formula-1 in a suitable solvent,
h) purifying the ambrisentan compound of formula-1 in a suitable solvent to provide pure ambrisentan.

The second aspect of the present invention is to provide pure ambrisentan compound of formula-1 having purity grater than 99.90 % by HPLC.
The third aspect of the present invention is to provide a process for the purification of ambrisentan, which comprises of crystallizing ambrisentan from a solvent selected from the group comprising of alcohol or a polar solvent or mixtures thereof.
The fourth aspect of the present invention is to provide a novel crystalline form of ambrisentan. The novel crystalline form of the present invention characterized by its PXRD pattern and IR spectrum.
The fifth aspect of the present invention is to provide a process for the preparation of novel crystalline form of ambrinsentan.
The sixth aspect of the present invention is to provide an improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a, which comprises of reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7 with suitable alcohol, in presence of a suitable acid catalyst in a suitable solvent, followed by crystallization from suitable hydrocarbon solvents.
The seventh aspect of the present invention is to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a as a solid.
The eighth aspect of the present invention is to provide a novel crystalline form of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a. The novel crystalline form of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester is characterized by its PXRD, IR and DSC thermogram.
The ninth aspect of the present invention is to provide a highly pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a and its use in the preparation of ambrisentan and its analogues like darusentan.

Advantageous of the present invention:
• Provides a commercially viable and eco friendly process for the preparation of ambrisentan and its intermediates.
• Provides highly pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester
• Provides (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as a solid and in crystalline form.
• Provides a novel crystalline form of ambrisentan
• Avoids the usage of ether solvents in the isolation steps.
• Provides highly pure ambrisentan
Brief Description of Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline form-M of
ambrisentan
Figure-2: Illustrates the IR spectrum of crystalline form-M of ambrisentan
Figure-3: Illustrates the powder X-ray diffraction pattern of crystalline form-1 of (S)-2-
hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester
Figure-4: Illustrates the IR spectrum of crystalline form-1 of (S)-2-hydroxy-3-methoxy-
3,3-diphenylpropionic acid methyl ester.
Figure-5: Illustrates the DSC of crystalline form-1 of (S)-2-hydroxy-3-methoxy-3,3-
diphenylpropionic acid methyl ester.
Figure-6: HPLC chromatogram of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid
methyl ester.
Figure-7: HPLC chromatogram of ambrisentan.
Detailed Description of the Invention:
As used herein, the term "Ambrisentan" refers to active S-isomer of ambrisentan.
As used herein, the term "lower alkyl" refers to a straight or branched or cyclic Q to C6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and isohexyl and the like.

As used herein, the "C5-C10 aliphatic hydrocarbon solvents" refers to pentane, hexane, heptane, octane, nonane and decane.
The present invention relates to an improved process for the preparation of ambrisentan. Ambrisentan is chemically known as (+)-(2iS)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid, which is represented by the following formula-1.

The first aspect of the present invention provides an improved process for the preparation of ambrisentan compound of formula-1, which comprises of the following steps; a) reacting the benzophenone compound of formula-2

Formula-2 with alkyl chloroacetate compound of formula-3

Formula-3 Wherein 'R' is lower alkyl group
in presence of a suitable base selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkoxide bases like sodium methoxide, potassium methoxide, sodium

tertiary butoxide and potassium tertiary butoxide, preferably sodium methoxide in a suitable ether solvents selected from diisopropyl ether, dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran, preferably tetrahydrofuran to provide 3,3-diphenyloxirane-2-carboxylic acid alkyl ester compound of formula-4,

which on in-situ treatment with methanol in presence of a suitable acid selected from paratoluene sulfonic acid, hydrochloric acid, oxalic acid and methane sulfonic acid to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-5,
Formula-5 b) hydrolyzing the alkyl ester compound of formula-5 with a suitable aqueous alkali metal hydroxides like sodium hydroxide, potassium hydroxide and lithium hydroxide and crystallizing from a suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof, to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6,


c) resolving the acid compound of formula-6 by treating it with a suitable resolving
agents selected from (S)-l-(4-nitrophneyl)ethylamine or L-proline methyl ester or its
salts, in a suitable solvent selected from alcohol solvents like methanol, ethanol,
isopropanol, 2-butanol; ester solvents like ethyl acetate, methyl acetate and propyl
acetate; ether solvents like diisopropyl ether, dibutylether, methyl tert-butyl ether,
dioxane and tetrahydrofuran or mixtures thereof, followed by crystallization from a
suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane;
aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures
thereof, to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound
offormula-7,

Formula-7
d) reacting the compound of formula-7 with suitable alcohol like methanol, ethanol or
isopropanol in presence of a suitable catalyst selected from sulphuric acid,
hydrochloric acid, thionylchloride, methane sulfonic acid and paratoluene sulfonic
acid, followed by isolation in a suitable solvent selected from C5-C10 aliphatic
hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene,
xylene; and cyclohexane or mixtures thereof, to provide the corresponding (S)-2-
hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-8,

Formula-8
e) purifying the alkyl ester compound of formula-8 using suitable alcoholic solvents
selected from methanol, ethanol, isopropanol, 2-butanol or mixtures thereof to
provide pure alkyl ester compound of formula-8,

f) reacting the pure alkyl ester compound of formula-8 with 4,6-dimethyl-2-
(methylsulphonyl)pyrimidine compound of formula-9

Formula-9 in presence of a suitable base selected from alkali metal hydride such as sodium hydride, potassium hydride; an alkali metal carbonate like sodium carbonate or potassium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal amide bases like lithium diisopropyl amide, lithium amide; alkoxide bases like sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide, preferably alkali metal carbonates like potassium carbonate in a suitable solvent selected from polar aprotic solvents like dimethyl formamide, dimethylacetamide, dimethyl sulfoxide and ketone solvents like acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, preferably polar aprotic solvent such as dimethyl formamide followed by isolation of ester compound of formula-10 by adding water,

Formula-10
g) hydrolyzing the ester compound of formula-10 with a suitable aqueous base selected
from alkali metal hydroxides like sodium hydroxide, potassium hydroxide and
lithium hydroxide; alkali metal carbonates like sodium carbonate, potassium
carbonate, sodium bicarbonate and potassium bicarbonate in a suitable solvent
selected from polar solvent like water; alcohol solvents like methanol, ethanol,
isopropanol and 2-butanol; ether solvents like diisopropyl ether, dibutylether, methyl
tert-butyl ether, dioxane and tetrahydrofuran or mixture thereof followed by isolation

of ambrisentan compound of formula-1 in a suitable ester solvent like ethyl acetate, methyl acetate and propyl acetate, h) purifying the ambrisentan compound of formula-1 in a suitable solvents selected from alcoholic solvent like methanol, ethanol, isopropanol or mixtures thereof to provide pure ambrisentan.
The second aspect of the present invention is to provide high pure ambrisentan compound of formula-1 having purity greater than 99.00%, preferably 99.50%, more preferably 99.90% by HPLC. The HPLC chromatogram of high pure ambrisentan is shown in figure-7.
The third aspect of the present invention is to provide a process for the purification of ambrisentan compound of formula-1, which comprises of the following steps,
a) dissolving the crude ambrisentan in a suitable solvent selected from alcohol solvents like methanol, ethanol, isopropanol, 2-butanol and/or water or mixture thereof by heating to reflux,
b) filtering the solution to remove extraneous matter,
c) cooling the reaction mixture to 25-35°C and stirred,
d) filtering the precipitated solid and washed with suitable solvent selected from alcohol solvents like methanol, ethanol, isopropanol, 2-butanol and/or water or mixture thereof,
e) drying the solid to get high pure ambrinsentan compound of formula-1
The fourth aspect of the present invention is to provide a novel crystalline form of ambrisentan compound of formula-1. The novel crystalline form of ambrisentan herein designated as "Form-M".
The novel crystalline form-M of ambrisentan is characterized by its strong X-ray peaks at about 7.54, 8.86, 12.29, 13.06, 14.13, 15.18, 18.2, 20.55, 22.91, 24.26, 26.86, 28.9, 36.54 and 40.45 ± 0.2 degrees two theta as illustrated in figure-1. The novel crystalline form-M of ambrisentan is also characterized by its Infrared spectrum peaks at

about 3057.6, 2965.8, 1752.6, 1559.2, 1493.2, 1446.0, 1406.5, 1379.8, 1313.4, 1192.7, 1075.5, 1001.7, 877.0, 701.1 611.9 cm-1 as illustrated in figure-2.
The fifth aspect of the present invention provides a process for the preparation of crystalline form-M of ambrisentan, which comprises of the following steps;
a) dissolving ambrisentan compound of formula-1 in a suitable alcoholic solvents like methanol, ethanol, isopropanol and 2-butanol and/or water or mixtures thereof at reflux temperature,
b) stirring the reaction mixture for 30 minutes at reflux,
c) cooling the reaction mixture to 25-35°C,
d) filtering the precipitated solid and washing with suitable alcoholic solvents like methanol, ethanol, isopropanol and 2-butanol and/or water or mixtures thereof,
e) drying the solid to get the crystalline form-M of ambrisentan.
The sixth aspect of the present invention provides a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a,
Which comprise of the following steps;
a) reacting the acid compound of formula-7

Formula-7 with methanol in presence of a suitable catalyst selected from sulphuric acid, hydrochloric acid, thionylchloride, methane sulfonic acid and paratoluene sulfonic acid,

b) stirring the reaction mixture for sufficient time to complete the reaction,
c) quenching the reaction mixture with water,
d) extracting the reaction mixture into chloro solvents like methylene chloride, chloroform or ester solvents like ethyl acetate, methyl acetate and isopropyl acetate,
e) distilling off the solvent completely under reduced pressure,
f) crystallizing the obtained residue using suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof.
The seventh aspect of the present invention provides (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as a solid.
The eight aspect of the present invention provides a novel crystalline form of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a. This novel crystalline form of formula-8a herein designated as "Form-1".
The novel crystalline form-1 of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a is characterized by its strong PXRD peaks at about 7.16, 10.94, 15.31, 15.72, 16.69, 17.42, 20.79, 22.01, 25.42, 25.88, 29.66, 34.98 and 41.96 ± 0.2 degrees two theta as illustrated in figure-3. The crystalline form-1 is also characterized by its IR spectrum peaks at about 3498, 3062, 2945, 1729, 1595, 1491, 1437, 1397, 1491, 1437, 1322, 1270, 1182, 1073, 730, 669 cm"1 as illustrate in figure-4 and also by DSC thermo gram as illustrated in figure-5.
The present invention also provides a process for the preparation of crystalline form-1 of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a, which comprises of the following steps;
a) dissolving (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a in a suitable alcoholic solvents like methanol, ethanol, isopropanol, butanol or mixtures thereof at reflux temperature of the solvent,
b) stirring the reaction mixture for 30 minutes at reflux,
c) cooling the reaction mixture to 10-15°C,

d) filtering the precipitated solid and washing with suitable alcoholic solvent,
e) drying the solid to get the crystalline form-1 of compound of formula-8a.
The ninth aspect of the present invention provides high pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a and its use in the preparation of ambrisentan and its analogues like darusentan.

Formula-8a
According to the present invention the highly pure compound of formula-8a is having purity grater than 95.00% by HPLC, preferably >98.00 % more preferably 99.50%. The highly pure compound of formula-8a obtained by preparing the compound of formula-8a as per the process disclosed in sixth aspect of the invention followed by crystallization in a suitable solvents selected from alcoholic solvent like methanol, ethanol, isopropanol, 2-butanol and polar solvents like water or mixtures thereof. The HPLC chromatogram of high pure intermediate compound of formula-8a is represented in figure-6.
XRD analysis of ambrisentan was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A0 and continuous scan speed of 0.0457min. FI-IR spectrum of ambrisentan was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of ambrisentan was carried out on Waters DSC Q-10 model differential scanning calorimeter.
The related substance of ambrisentan and its intermediate compounds were analyzed by HPLC using the following conditions:
Column: symmetry-C18 150 X 2.1mm; Flow rate: 0.8 ml/min; wavelength: PDA; Temperature: 25°C; Load: 20 u,l; Run time: 45 min; and using 0.02M potassium dihydrogen orthophosphate and acetonitrile in the ration 1:1 as diluent.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl
ester compound of formula-5a:
Mixture of benzophenone (100 grams) and methyl chloroacetate (84 grams) in tetrahydrofuran (160 ml) was added to a cooled mixture of tertrahydrofuran and sodium methoxide at below -4°C in 90 minutes, stirred for 30 minutes at -10°C to -5°C. The reaction mixture temperature was raised to 25-35°C, quenched with water and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. The organic layer was distilled under reduced pressure at 60°C and methanol was added to the obtained residue then methanol was distilled off completely. The reaction mixture cooled to 25-35°C and methanol (280 ml) was added to it. Paratoluene sulfonic acid (4 grams) was added to the above reaction mixture. The reaction mixture was stirred for 2 hours at 25-35°C and then cooled to 0-5°C and stirred 45 minutes. The obtained solid was filtered, washed with methanol and then dried at 50-60°C to get the title compound. Yield: 110 grams M.R: 92-96°C
Example-2: Preparation of 2-hydroxy-3-methoxy-3,3-diphenyIpropionic acid compound of formuIa-6:
Mixture of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (100 grams) and aqueous sodium hydroxide solution (22 grams in 200 ml of water) was heated to 95-100°C and stirred for 120 minutes. The reaction mixture was cooled to 40-45°C and quenched with water. The pH of the reaction mixture was adjusted to 1.3 with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent from the ethyl acetate layer was distilled off completely under reduced pressure at 60°C. The reaction mixture was cooled to 40°C and cyclohexane (230 ml) was added. The reaction mixture was cooled to 25-35°C and stirred for 40 minutes at 25-35°C. The solid formed

was filtered off and washed with cyclohexane then dried at 60-70°C to get the title compound. Yield: 92 grams M.R: 108-112°C
Example-3: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formuIa-7:
Methanolic sodium methoxide solution (33 grams) was added to the solution of L-proline methyl ester hydrochloride (30.38 grams) in methanol (28 ml), stirred for 15 minutes at 25-35°C then filtered to remove the unwanted solid. The solvent from the reaction mixture was distilled off under reduced pressure at 60°C. The solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6 (50 grams) in methyltertiarybutylether (530 ml) was added to the above residue. The reaction mixture was heated to reflux temperature (55-60°C), stirred for 45 minutes and then cooled to 25-35°C and further stirred for 30 minutes. The solid separated was filtered off and washed with MTBE. Water (220 ml) was added to the filtrate and pH was adjusted to 1.2 with hydrochloric acid. The aqueous and organic layers were separated and then aqueous layer extracted with MTBE. The total organic layer washed with water and then distilled off the solvent completely under reduced pressure at 60°C. Toluene (100 ml) was added to the residue, heated to reflux temperature for 15 minutes then cooled to 25-35°C and stirred for 45 minutes. The obtained solid was filtered off and washed with toluene then dried at 50-60°C to get the title compound. Yield: 17 grams M.R:118-122°C. S.O.R: + 26° (C= 0.5; MeOH)
Example-4: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7
The title compound is prepared analogues manner to example-3 using the ethyl acetate as a solvent in place of methyl tertiary butyl ester. Yield: 16.5 grams; S.O.R: + 21° (C= 0.5; MeOH)

Example-5: preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenyIpropionic acid methyl ester compound of formula-8a:
Paratoluene sulfonic acid (7.9 grams) was added to a mixture of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7 (50 grams) and methanol (150 ml) at 25-35°C then stirred for 48 hours at 25-35°C. The reaction mixture was quenched with cooled water (200 ml) and methylene chloride (150 ml). The aqueous and organic layers were separated and aqueous layer was extracted with methylene chloride. The organic layer combined, washed with sodium bicarbonate solution and the solvent from the organic layer distilled off under reduced pressure at 55°C. Cyclohexane (50 ml) was added to the above residue and stirred at 30 minutes at 45-50°C. The reaction mixture was initially cooled to 25-30°C and then to -5 to 0°C. The reaction mixture was stirred for 60 minutes at -5 to 0°C. The obtained solid was filtered and washed with chilled cyclohexane. The solid was dried at 25-35°C to get the title compound. The PXRD, IR and DSC of the obtained solid compound is similar to the crystalline form-I of formula-8a.
Yield: 35 grams; M.R: 58-60°C S.O.R: + 39.3° (C=0.5; MeOH) Purity: 98.5 % by HPLC
Example 6 to 9: preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formu!a-8a
The title compound S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester has been prepared analogues manner to example-5 using the appropriate amount starting material, methanol and catalyst in the ratio which are mentioned in the following table.


Example-10: Purification of compound of formula-8a.
A mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (5 grams) and 2-butanol (50 ml) was heated to reflux temperature. The reaction mixture was stirred for 30 minutes at 88-92°C and then cooled to 10-15°C. The precipitated solid was filtered, washed with 2-butanol and then dried to get the high pure title compound. Yield: 4.2 grams Purity: 99.10% by HPLC
Example-11: Preparation of Crystalline form-1 of compound of formula-8a.
A mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (5 grams) and isopropyl alcohol (50 ml) was heated to reflux temperature. The reaction mixture was stirred for 30 minutes at 75-80°C and then cooled to 10-15°C. The precipitated solid was filtered, washed with isopropyl alcohol and then dried to get the high pure title compound. Yield: 4.0 grams;
Example-12: Preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid methyl ester compound of formuIa-lOa:
Mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound formula-8 (50 grams), dimethyl formamide (500 ml) and potassium carbonate (12 grams) was stirred at 40 minutes at 25-35°C. 4,6-dimethyl-2-(methylsulphonyl) pyrimidine (34.5 grams) was added and heated to 90-95°C. The reaction mixture was cooled to 25-35°C. Water (250 ml) was added and stirred for 60 minutes. The solid obtained was filtered, washed with water and then dried at 60-70°C to get the title compound. Yield: 55 grams M.R: 130-140°C S.O.R: +135.8° (C= 0.5; MeOH)
Example-13: Preparation of ambrisentan compound of formula-1:
Aqueous sodium hydroxide solution (10 grams in 250 ml of water) was added to the mixture of 1,4-dioxane (500 ml) and (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-

methoxy-3,3-diphenylpropanoic acid methyl ester (50 grams) compound of formula-10a at 25-35°C, then heated to 85-90°C and stirred for 3 hours. The reaction mixture was cooled to 25-35°C and water (500 ml) was added. The reaction mixture was washed with ethylacetate. The pH of aqueous layer was adjusted to 1.8 with hydrochloric acid at 25-35°C. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off under reduced pressure at 60°C and then cooled to 0-5°C. The reaction mixture was stirred for 60 minutes at 0-5°C. The obtained solid was filtered, washed with chilled ethyl acetate and dried at 60-70°C to get the ambrisentan. Yield: 36 grams
Example-14: Purification of ambrisentan:
Mixture of ambrisentan (30 grams), isopropyl alcohol (189 ml) and methanol (21 ml) was heated to reflux. The reaction mixture was filtered and washed with a mixture of isopropyl alcohol and methanol. The filtrate was cooled to 25-35°C and stirred for 45 minutes. The solid obtained is filtered, washed with a mixture of isopropyl alcohol and methanol then dried at 60-70°C to get high pure ambrisentan. Yield: 22 grams
S.O.R: + 183.37° (C = 0.5; MeOH) Purity: 99.92% by HPLC
Example-15: Purification of ambrisentan:
Mixture of ambrisentan (30 grams) and isopropyl alcohol (210 ml) was heated to 80-85°C. The reaction mixture was filtered at 80-85°C and washed with isopropyl alcohol. The filtrate was cooled to 25-3 5 °C and stirred for 45 minutes. The solid obtained is filtered, washed with isopropyl alcohol then dried at 60-70°C to get high pure ambrisentan. Yield: 21.5 grams Purity: 99.90% by HPLC.

We claim:
1) An improved process for the preparation of ambrisentan compound of formula-1,
which comprises: a) reacting a benzophenone compound of formula-2

with alkyl chloroacetate compound of formula-3

Wherein R is selected from lower alkyl group
in the presence of a base and in a suitable solvent to provide 3,3-diphenyloxirane-2-
carboxylic acid alkyl ester compound of formula-4,

which on in-situ treatment with methanol in presence of a suitable acid to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-5,


b) hydrolyzing the alkyl ester compound of formula-5 in presence of a suitable base in a
suitable solvent, followed by crystallization from suitable hydrocarbon solvents to
provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6,

c) resolving the acid compound of formula-6 by treating it with a suitable resolving agents in a suitable solvent, followed by crystallization from suitable hydrocarbon solvents to provide (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid compound offormula-7,
d) treating the compound of formula-7 with suitable alcohol in presence of a suitable acid catalyst followed by isolation in a suitable hydrocarbon solvents, to provide corresponding (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid alkyl ester compound of formula-8,
e) purifying the alkyl ester compound of formula-8 using suitable solvents to provide pure alkyl ester compound of formula-8,

f) reacting the pure alkyl ester compound of formula-8 with 4,6-dimethyl-2
(methylsulphonyl)pyrimidine compound of formula-9

Formula-9 in presence of a suitable base in a suitable solvent followed by isolation ester compound of formula-10 by adding water,

g) hydrolyzing the ester compound of formula-10 with a suitable base in a suitable
solvent followed by isolation in a suitable ester solvent, to provide the ambrisentan
compound of formula-1,
h) purifying the ambrisentan in a suitable solvent to provide pure ambrisentan.
2) The process of claim 1, comprising at least one of the following;
i) a step a) wherein base is selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkoxide bases like sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide; and a suitable solvent is ether solvent, selected from dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran; and a suitable acid is selected from paratoluene sulphonic acid, hydrochloric acid, oxalic acid and methane sulfonic acid; ii) a step b) wherein the base is selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide and lithium hydroxide and suitable solvent is polar solvent like water; hydrocarbon solvent is selected from C5-C10 aliphatic

hydrocarbons like hexane, hepatane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof;
iii) a step c) wherein the resolving agent is selected from L-proline methyl ester or its salts; a suitable solvent is selected from alcohol solvents such as methanol, ethanol, isopropanol, 2-butanol; ester solvents such as ethyl acetate, methyl acetate and propyl acetate; ether solvents such as diisopropyl ether, dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran or mixture thereof and hydrocarbon solvents selected from C5-C10 aliphatic hydrocarbons like hexane, hepatane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof,
iv) a step d) wherein the suitable solvent is alcohol solvents selected from methanol, ethanol or isopropanol and catalyst is selected from sulphuric acid, hydrochloric acid, thionylchloride, methane sulfonic acid and paratoluene sulfonic acid; hydrocarbon solvent selected from C5-C10 aliphatic hydrocarbons like hexane, hepatane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof;
v) a step e) wherein the suitable solvent is alcohol solvent selected from methanol, ethanol, isopropanol, 2-butanol or mixtures thereof;
vi) a step f) wherein the base is selected from alkali metal hydride such as sodium hydride, potassium hydride, an alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal amide bases like lithium diisopropyl amide, lithium amide; alkoxide bases like sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide and solvent is selected from polar aprotic solvent such as dimethyl formamide, dimethylacetamide, dimethyl sulfoxide; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone;
vii)a step g) wherein suitable base is selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; suitable solvent selected from polar solvent like water;

alcohol solvents like methanol, ethanol, isopropanol and 2-butanol; ether solvents like diisopropyl ether, dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran or mixture thereof; suitable ester solvent is selected from ethyl acetate, methyl acetate and propyl acetate; viii) a step h) wherein the suitable solvent is alcohol solvent selected from methanol, ethanol, isopropanol, butanol or mixtures thereof.
3) A process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-
methoxy-3,3-diphenylpropanoic acid methyl ester compound of formula-10a,

which comprises of reacting (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a with 4,6-dimethyl-2-(methylsulphonyl) pyrimidine compound of formula-9 in presence of a suitable base in a suitable solvent selected from ketone solvents or polar aprotic solvents or mixtures thereof, followed by isolation of ester compound of formula-10a by adding water.
4) The process of claim 3, wherein the base is selected from alkali metal hydride such as sodium hydride, potassium hydride, an alkali metal carbonate like sodium carbonate or potassium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal amide bases like lithium diisopropyl amide, lithium amide; alkoxide bases like sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide, and polar aprotic solvents selected from dimethyl formamide, dimethylacetamide, dimethyl sulfoxide; polar solvents like water; ketone solvents selected from acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone.
5) A process for the preparation of ambrisentan, which comprises of the following steps; a) reacting the benzophenone compound of formula-2 with methyl chloroacetate
compound of formula-3a in presence of sodium methoxide in tetrahydrofuran to

provide 3,3-diphenyloxirane-2-carboxylic acid methyl ester compound of formula-4a, which is treated in-situ with methanol in presence of a paratoluene sulfonic acid to provide 2-hydroxy-3-methoxy -3,3-diphenylpropionic acid methyl ester compound of formula-5a,
b) hydrolyzing the methyl ester compound of formula-5a with aqueous sodium hydroxide followed by crystallization from cyclohexane, to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6,
c) resolving the acid compound of formula-6 by treating it with L-proline methyl ester in methyl tert-butyl ether followed by its crystallization from toluene, to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7,
d) reacting the compound of formula-7 with methanol and paratoluene sulfonic acid followed by isolation in cyclohexane, to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a,
e) purifying the methyl ester compound of formula-8a using 2-butanol to provide pure methyl ester compound of formula-8a,
f) reacting the pure methyl ester compound of formula-8a with 4,6-dimethyl-2-(methylsulphonyl)pyrimidine compound of formula-9 in presence of potassium carbonate in dimethyl formamide followed by isolation of ester compound of formula-10a by adding water,
g) hydrolyzing the ester compound of formula-10a with aqueous sodium hydroxide in dioxane followed by isolation of ambrisentan using ethyl acetate.
6) A process for the purification of ambrisentan compound of formula-1, which comprises;
a) dissolving the crude ambrisentan in a suitable solvent selected from alcohol solvents like methanol, ethanol, isopropanol, 2-butanol and/or water or mixture thereof by heating to reflux,
b) filtering the solution to remove extraneous mater,
c) cooling the reaction mixture to 25-35°C and stirred,

d) filtering the precipitated solid and washing with suitable solvent selected from alcohol solvents like methanol, ethanol, isopropanol, 2-butanol and/or water or mixture thereof,
e) drying the solid to get high pure ambrinsentan compound of formula-1.
7) A novel crystalline form-M of ambrisentan compound of formula-1 characterized by
any one of the following;
a) its strong X-ray peaks at about 7.54, 8.86,12.29,13.06, 14.13,15.18,18.2, 20.55, 22.91, 24.26, 26.86, 28.9, 36.54 and 40.45 ± 0.2 degrees two theta as illustrated in figure-1,
b) its IR spectrum peaks at about 3057.6, 2965.8, 1752.6, 1559.2, 1493.2, 1446.0, 1406.5, 1379.8, 1313.4, 1192.7, 1075.5, 1001.7, 877.0, 701.1 611.9 crn1 as illustrated in figure-2.
8) A novel process for the preparation of crystalline form-M of ambrisentan compound
of formula-1, which comprises of the following steps;
a) dissolving ambrisentan compound of formula-1 in a suitable alcoholic solvents like methanol, ethanol, isopropanol and 2-butanol and/or water or mixtures thereof at reflux temperature,
b) stirring the reaction mixture for 30 minutes at reflux,
c) cooling the reaction mixture to 25-35°C,
d) filtering the precipitate solid and washed with suitable alcoholic solvents like methanol, ethanol, isopropanol and 2-butanol and/or water or mixtures thereof,
e) drying the solid to get the crystalline form-M of ambrisentan.

9) (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as a solid.
10) The crystalline form-1 of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester is characterized by any one of the following;

a) by its strong PXRD peaks at about 7.16, 10.94, 15.31, 15.72, 16.69, 17.42, 20.79, 22.01, 25.42, 25.88, 29.66, 34.98 and 41.96 ± 0.2 degrees two theta as illustrated in figure-3,
b) its IR spectrum peaks at about 3498, 3062,2945,1729,1595, 1491,1437,1397,

1491, 1437,1322,1270,1182, 1073, 730, 669 cm-1 as illustrated in figure-4, c) its DSC endothermic peak at 63.20°C as illustrated in figure-5.
11) A process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a, which comprises of the following steps;
a) reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of
formula-7 with methanol in presence of suitable acid catalyst selected from
sulphuric acid, hydrochloric acid, thionylchloride, methane sulfonic acid and
paratoluene sulfonic acid,
b) stirring the reaction mixture for sufficient time to complete the reaction,
c) quenching the reaction mixture with water,
d) extracting the reaction mixture into chloro solvents like methylene chloride,
chloroform; ester solvents like ethyl acetate, methyl acetate and isopropyl acetate,
e) distilling off the solvent completely under reduced pressure,
f) crystallizing the obtained residue using suitable hydrocarbon solvents like
toluene, cyclohexane and heptane.
g) purifying of formula-8a using alcohol solvents like methanol, ethanol,
isopropanol, butanol or mixtures thereof to provide pure compound of formula-8a.
12)(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound having purity greater than 98.50 % by HPLC.
13) The use of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester as claimed in any one of claim 9 or claim 10 or claim 12 as intermediate or as a starting material in the preparation of ambrisentan and its analogues like darusentan.