process involves the usage of sodium hydride which is not recommendable for a large scale commercial process.
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 Darusentan. 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 darusentan 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 darusentan 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 hs quality. This when used in the subsequent stages provided darusentan in high yields and of high purity.
Organic Process Research & Development 2001, 5,16-22 also disclosed a process for the preparation of darusentan by the condensation of (S)-p-chlorophenylethylammonium-(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate with 4,6-dimethoxy-2-methyl-sulfonylpyrimidine in presence of lithium amide in dimethylformamide.
Moreover the reported processes of darusentan and its intermediates involve the usage of ether solvents for final isolation, which is commercially not recommendable.
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 pattem in fingerprint region, and solid state

NMR spectrum. One crystalline form may give rise to thermal behavior different from 'o--
that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compovmds 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 darusentan and its pharmaceutically acceptable salts.
Hence there is a need in the art for an improved process for the preparation darusentan by avoiding the final resolution.
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 darusentan through a high pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester.
Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of darusentan 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 compoimd 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 compoimd of formula-8 using suitable alcoholic solvents,
f) reacting the alkyl ester compound of formula-8 with 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine compound of formula-9 in presence of a suitable base in a suitable solvent to provide the ester compound of formula-10,
g) hydrolyzing the ester compoimd of formula-10 in presence of a suitable aqueous base in a suitable solvent followed by dissolving the obtained residue in a suitable solvent and adding water to provide darusentan compound of formula-1,
h) purifying the darusentan compound of formula-1 in a suitable solvent to provide pure darusentan.
The second aspect of the present invention is to provide pure darusentan 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 darusentan, which comprises of crystallizing darusentan 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 darusentan. 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 darusentan.

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 alkyl ester compoimd of formula-8, 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.
Advantageous of the present invention:
• Provides a commercially viable and eco friendly process for the preparation of darusentan and its intermediates.
• Provides highly pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester
• Provides a novel crystalline form of darusentan
• Avoids the usage of ether solvents in the isolation steps.
• Provides highly pure darusentan.
Brief Description of Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline form-M of
darusentan
Figure-2: Illustrates the IR spectrum of crystalline form-M of darusentan
Figure-3: Illustrates the HPLC chromatogram of darusentan.
Detailed Description of the Invention:
As used herein, the term "darusentan" refers to active S-isomer of darusentan.
As used herein, the term "lower alkyl" refers to a straight or branched or cyclic Ci 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 Darusentan. Darusentan is chemically known as (+)-(25)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid, which is represented by the following formula-1.

OCH,
OCH3 Formula-1
The first aspect of the present invention provides an improved process for the
preparation of damsentan compound of formula-1, which comprises of the following
steps;
a) reacting the benzophenone compound of formula-2

Formula-2 with alkyl chloroacetate compoimd of formula-3

O CI,
OR 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,


ROOC
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-S,
/
ROOC
Formula-S b) hydrolyzing the alkyl ester compound of formula-5 with a suitable aqueous alkali metal hydroxides like sodium hydroxide, potassium hydroxide and lithium hydroxide followed by 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.

HOOC V^
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 hydrocarbon solvents 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 of formula-7.

HOOC "^^^
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 hydrocarbon solvents 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,

ROOC V,^
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-dimethoxy-2-(methylsulphonyl)pyrimidine compound of 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, dimethyl acetamide, dimethyl sulfoxide and ketone solvents like acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, preferably ketone solvent such as acetone, followed by crystallization from a suitable alcoholic solvents like methanol, ethanol and isopropanol to provide

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 dissolving the obtained crude in a suitable ketone solvent selected from acetone,

methyl isobutylketnone and adding water to provide darusentan compound of formula-1, h) purifying the darusentan compound of formula-1 in a suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropanol or mixtures thereof to provide pure darusentan.
The second aspect of the present invention is to provide highly pure darusentan compound of formula-1 having purity greater than 99.00%, preferably 99.50%, more preferably 99.90% by HPLC. The HPLC chromatogram of highly pure darusentan is shown in figure-3.
The third aspect of the present invention is to provide a process for the purification of darusentan compound of formula-1, which comprises of the following steps,
a) dissolving the crude darusentan 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 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 darusentan compound of formula-1
The fourth aspect of the present invention is to provide a novel crystalline form of darusentan compound of formula-1. The novel crystalline form of darusentan herein designated as "Form-M".
The novel crystalline darusentan form-M is characterized by its strong X-ray peaks at about 5.02, 11.25, 13.89, 16.28, 19.3, 20.88, 22.72, 22.86, 24.11, 24.41, 28.54, 30.23 and 33.72 ± 0.2 degrees two theta as illustrated in figure-1. The novel crystalline darusentan form-M is also characterized by its Infi-ared spectrum peaks at about 3118.2,



with suitable alcohol selected from methanol, ethanol, isopropanol 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 hydrocarbon solvents like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof
XRD analysis of darusentan was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FI-IR spectrum of darusentan was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of darusentan was carried out on Waters DSC Q-10 model differential scanning calorimeter.
The related substance of darusentan and its intermediate compounds were analyzed by HPLC using the following conditions:
Column: symmetry-CIS 150 X 2.1mm; Flow rate: 0.8 ml/min; wavelength: PDA; Temperature: 25°C; Load: 20 jxl; 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-diphenylpropioiiic 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
ExampIe-2: Preparation of 2-hydroxy-3-methoxy-3,3-diphenyIpropionic acid compound of formula-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 formula-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 fi-om 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 fiirther 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-diphenylpropionic 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: 98.50 % by HPLC
Example 6 to 9: preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formuIa-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 Formula-7 Methanol Acid Catalyst Yield

Acid used Qty.

6 5 grams 20 ml SOCI2 0.10 grams 4.5 grams
7 5 grams 50 ml H2SO4 0.190 grams 4.5 grams
8 40 grams - Methanolic HCl 160.0 ml 38 grams
9 10 grams 30 ml Methane sulfonic acid 0.88 grams 10 grams

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 (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid methyl ester compound of formula-lOa:
Mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a (50 grams), acetone (500 ml) and potassium carbonate (12 grams) was stirred for 40 minutes at 25-35°C. 4,6-dimethoxy-2-(methylsulphonyl) pyrimidine (29.25 grams) was added to the above reaction mixture, heated to 55-60°C and stirred for 10 hours. The reaction mixture was cooled to 25-35°C, filtered and washed with acetone. The filtrate was distilled off under reduced pressure at 50°C. The reaction mixture was cooled to 25-35°C and quenched with water. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off completely under reduced pressure at 60°C. The reaction mixture cooled to 45°C and methanol was added then distilled off methanol. Methanol (100 ml) was added to the obtained residue and heated to 55-60°C and stirred for 30 minutes. The reaction mixture was cooled to 20-25°C and stirred for 45 minutes. The obtained solid was filtered off and washed with methanol. The solid was dried at 50-60°C to get the title compound. Yield: 41 grams M.R: 108-112°C S.O.R: + 115° (C=0.5; MeOH)
ExampIe-12: Preparation of darusentan compound of formula-1:
Aqueous sodium hydroxide (5.59 grams in 75 ml of water) was added to the mixture of (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid methyl ester compound of formula-10a (30 grams) and methanol

(300 ml) at 25-35°C. The reaction mixture was heated to 55-60°C and stirred for 3 hours. The solvent from the reaction mixture was distilled off under reduced pressure at 60°C. The reaction mixture was cooled to 25-35°C and quenched with water. The reaction mixture was washed with ethyl acetate. The pH of aqueous layer was adjusted to 5.8 with aqueous acetic acid and extracted with ethyl acetate. The ethyl acetate was distilled off completely from the reaction mixture under reduced pressure at 60°C. Then the reaction mixture was cooled to 40°C, acetone was added and then distilled off the acetone completely. The obtained residue dissolved in acetone and water (300 ml) was slowly added to it. The reaction mixture was stirred for 45 minutes at 25-35°C. The solid obtained was filtered and washed with water. The solid was dried at 60-70°C to get the title compound. Yield: 27 grams M.R: 166-170°C S.O.R: + 144.0° (C= 0.5; MeOH)
Example -13: Purification of darusentan:
A mixture of darusentan (10 grams) and isopropyl alcohol (30 ml) was heated to 80-85°C temperature. The reaction mixture was filtered at 75-80°C to remove the extraneous matter. The filtrate was initially cooled to 20-25°C and then cooled to 0-5°C. The reaction mixture was stirred for 30 minutes at 0-5 °C. The precipitated solid was filtered and washed with isopropyl alcohol then dried to get the high pure darusentan. Yield: 6.5 grams: Purity: 99.96% by HPLC

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 mixtures 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 solvent 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; alcoholic solvents such as methanol, ethanol, isopropanol and butanol;

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 dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran or mixtures thereof; suitable ketone solvent like acetone and methyl isobutyl ketone;
viii) a step h) wherein the suitable solvent is alcohol solvent selected from methanol, ethanol, isopropanol, butanol or mixtures thereof

which comprises of reacting (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a with 4,6-dimethoxy-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 crystallization of ester compound of formula-10a from a suitable alcoholic solvent.
4) The process of claim 3, wherein the base is selected from alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, an alkali metal carbonate like sodium carbonate or potassium carbonate; alkali earth 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; ketone solvents selected from

acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone; alcoholic solvent selected from methanol, ethanol, isopropanol and butanol.
5) A process for the preparation of darusentan, 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 its crystallization from cyclohexane to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of fonnula-6,,
c) resolving the acid compovmd 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 formuIa-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-dimethoxy-2-(methylsulphonyl)pyrimidine compound of formula-9 in presence of potassium carbonate in acetone followed by crystallization from methanol to provide the ester compound of formula-10a,
g) hydrolyzing the ester compound of formula-10a with aqueous sodium hydroxide in methanol followed by dissolving the obtained residue in acetone and isolating the darusentan compound of formula-1 by addting water,
h) purifying the darusentan in isopropanol gives highly pure darusenetan compound of formula-1.

6) A process for the purification of darusentan compound of formula-1, which
comprises;
a) dissolving the crude darusentan 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 darusentan compound of formula-1.

7) A process according to claim 5 or 6) wherein the obtained darusentan having purity greater than 99.95% by HPLC.
8) A novel crystalline form-M of darusentan compound of formula-1 characterized by any one of the following

a) its strong X-ray peaks at about 5.02, 11.25, 13.89, 16.28, 19.3, 20.88, 22.72, 22.86, 24.11, 28.54, 30.23 and 33.72 ± 0.2 degrees two theta as illustrated in figure-1
b) its IR spectrum peaks at about 3118.2, 3004.6, 2963.5, 2835.9, 1754.3, 1593.7, 1486.2, 1447.1, 1316.8, 1218.5, 1130.5, 1094.5, 1072.3, 990.9, 825.1, 754.1, 703.2, 630.9 and 594.9 cm'' as illustrated in figure-2.
9) A novel process for the preparation of crystalline form-M of darusentan compound of
formula-1, which comprises the following steps;
a) dissolving darusentan compound of formula-1 in a suitable alcoholic solvent 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 darusentan.
10) A process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-8, which comprises of the following steps;
a) reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of
formula-? with suitable alcohol selected from methanol, ethanol and isopropanol
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 solvent like toluene, cyclohexane and heptane,
g) purifying the compound of formula-8 using alcohol solvent like methanol,
ethanol, isopropanol, butanol or mixtures thereof to provide pure compoimd of
formula-8.