Field of the Invention:

The present invention relates to an improved process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid and its intermediate compounds. The (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid is commonly known as Ambrisentan, which is represented by the following structural 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.

Background of the Invention:

Ambrisentan and its pharmaceutically acceptable salts are disclosed in US 5932730. The disclosed process comprising of reacting benzophenone with methyl chloroacetate in the presence of sodium methoxide in tetrahydrofuran provides 3,3- diphenyl oxirane-2-carboxylic acid methyl ester, which on in-situ treatment with methanol and BF3 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 or (4-nitrophenyl)ethylamine to provide (S)-2-hydroxy-3-methoxy- 3,3-diphenylpropionic acid. The conversion of this ester intermediate into ambrisentan has not been disclosed in the above said patent.

Drugs of future 2005, 30(8), 765-770 disclosed the process for the preparation of racemic ambrisentan. The disclosed process comprising of, reacting 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester with 4,6-dimethyl-2-(methylsulfonyl) pyrimidine in presence of potassium carbonate in dimethylformamide, followed by hydrolysis with aqueous potassium hydroxide in dioxane to provide racemic ambrisentan. Thus obtained racemic ambrisentan can be converted into active compound by resolving with chiral amines, but does not disclose/specify any amine salts for the resolution.

Organic Process Research & Development 2001, 5, 16-22 reported the process for the resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid intermediate with L-methyl prolinate and (S)-l-(4-nitrophenyl)ethyl amine. The disadvantage with both the auxiliaries was that they are extremely expensive and could not be completely recycled. Resolution using (S)-l-(4-chlorophenyl) ethylamine proved to be a better alternative. But it can not be used at an industrial scale due to its high cost.

An article published in 'Research Disclosure' disclosed the process for the preparation of ambrisentan. The disclosed 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 methyl tertiary butyl ether. The ether layer is concentrated further the obtained crude was isolated using petroleum ether to provide pure ambrisentan. Even though this process avoids the esterification and hydrolysis steps, the purity and yield of the obtained ambrisentan is very less and in general the usage of amide bases is not recommendable in commercial scale to avoid the formation of impurities.

(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester has been reported as an oil in the prior-art. In the present invention the said compound was isolated as a crystalline solid which not only improved the yields, but also its quality. Thus the usage of said compound in the subsequent stages provided ambrisentan in high yields and high purity.

The aforesaid processes of prior-art disclosed the usage of L-proline methyl ester as a chiral resolution agent, which provides less percentage of required isomer of intermediate compound of ambrisentan, resulting the decrease in the yield and purity of the ambrisentan.

Henceforth, there is a need to develop an alternate process for the preparation of ambrisentan, which enhances the yield and purity of the ambrisentan and also should overcome the problems mentioned in the prior-art processes.

In the present invention we have surprisingly found that the usage of chiral reducing agent in the presence of chiral catalyst provides more than 95 percent of the required isomer of the intermediate compound of ambrisentan which enhances the yield and purity of the final compound (ambrisentan).

Brief Description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6, comprising of, oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5 with a suitable oxidizing agent in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6.

The second aspect of the present invention is to provide a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7 comprising of, reducing the keto compound of formula-6 with a suitable chiral reducing agent in presence of a chiral catalyst in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7.

The third aspect of the present invention is to provide an improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5 with a suitable oxidizing agent in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6,

b) reducing the keto compound of formula-6 with a suitable chiral reducing agent in presence of a chiral catalyst in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7.

c) optionally, purifying the compound obtained in step-b) from a suitable hydrocarbon solvent to provide pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7.

The fourth aspect of the present invention is to provide an improved process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid compound of formula-1, which comprising of the following steps:

a) reacting the benzophenone compound of formula-2 with chloroacetic acid derivative compound of formula-3 in presence of a suitable base in a suitable solvent to provide 3,3-diphenyloxirane-2-carboxylic acid derivative compound of formula-4, which is reacted in-situ with alcohol in presence of a suitable acid to provide 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5,

b) oxidizing the compound of formula-5 with a suitable oxidizing agent in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6,

c) reducing the keto compound of formula-6 with a suitable chiral reducing agent in the presence of a chiral catalyst in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7,

d) reacting the compound of formula-7 with 4,6-dimethyl-2-(methylsulphonyl) pyrimidine compound of formula-8 in presence of a suitable base in a suitable solvent and isolating the compound by addition of water to give (+)-(2S)-2-[(4,6-dimethyIpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid derivative compound of formula-9,

e) optionally, hydrolyzing the compound of formula-9 in presence of a suitable aqueous base in a suitable solvent followed by isolation of (+)-(2S)-2-[(4,6-dimethylpyrirmdin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid compound of formula-1 in a suitable solvent, f) optionally, purifying the compound obtained in step-e) in a suitable solvent to provide pure (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid compound of formula-1.

The fifth aspect of the present invention is to provide a process for the preparation of Darusentan compound of formula-lb, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5 with a suitable oxidizing agent in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6,

b) reducing the keto compound of formula-6 with a suitable chiral reducing agent in presence of a chiral catalyst in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7,

c) reacting the compound of formula-7 with 4,6-dimethoxy-2-(methylsulphonyl) pyrimidine compound of formula-10 in presence of a suitable base in a suitable solvent to provide (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3- methoxy-3,3-diphenylpropanoic acid derivative compound of formula-11,

d) optionally, hydrolyzing the compound obtained in step-c) in presence of a suitable aqueous base in a suitable solvent to provide Darusentan compound of formula-lb.

Advantages of the present Invention:

• Provides a commercially viable and eco friendly process for the preparation of ambrisentan and its intermediates with high yields and purity.
• Avoids the usage of chiral auxiliary like L-proline methyl ester, which provides only 50% of the required isomer.
• Avoids the usage of expensive chiral auxiliaries
• Provides highly pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester
• Reduces the number of steps of the process

Detailed Description of the Invention:

The present invention relates to an improved process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid and its intermediate compounds.

As used herein the term "ester solvents" refers to ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" refers to tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether and dioxane; "hydrocarbon solvents" refers to toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" refers to dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" refers to acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" refers to methanol, ethanol, n-propanol, isopropnol, n-butanol and isobutanol; "chloro solvents" refers to dichloromethane, chloroform and ethylene dichloride; polar solvent like water and mixture thereof.

As used herein the term acid refers to "inorganaic acid" such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and HCIO4; and "organic acid" refers to formic acid, acetic acid, oxalic acid, maleic acid, citric acid, propionic acid, p-toluene sulphonic acid, methane sulphonic acid and benzene sulphonic acid.

The term "base" herein the present invention is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine, dimethyl amino pyridine and pyridine.

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "C1-12 alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl and the like.

The suitable chiral reducing agent is selected from P-chlorodiisopinocampheyl borane (DIP Chloride) alone or reducing agent like, borane THF or borane DMS and in combination with a chiral catalyst like (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo(l,2-c)(l,3,2)oxazaborole (herein after referred as "R-Methyl CBS") or R-Butyl CBS or R-Phenyl CBS and the like.
The suitable oxidizing agent is selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride.

The first aspect of the present invention is to provide a process for the preparation of 2-oxo-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-6 comprising of, oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5 with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6.

In a preferred embodiment of the present invention provides a process for the preparation of 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a comprising of oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-5 a with sodium hypochlorite in dichloromethane to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a.

The second aspect of the present invention is to provide a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7 comprising of, reducing the keto compound of formula-6 with a suitable chiral reducing agent selected from Borane-THF or Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (1,2-c)(l,3,2) oxazaborolidine (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent selected from dichloromethane, toluene, xylene, THF or ethyl acetate to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7.

In a preferred embodiment 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-7a comprising of, reducing the keto compound of formula-6a with Borane-DMS in the presence of R-Methyl CBS in toluene to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a.

The third aspect of the present invention is to provide an improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7,

wherein, R is H or C1-12 alkyl, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5,

wherein, R is H alkyl,

with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenyl propionic acid derivative compound of formula-6,

b) reducing the keto compound of formula-6,

formula-6 wherein, R is H or C1-12 alkyl,

with a chiral reducing agent such as Borane-THF or Borane-DMS optionally in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)( 1,3,2) oxazaborolidine (R-Methyl CBS) or R-Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent like dichloromethane, toluene, xylene, THF or ethyl acetate to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7, c) optionally, purifying the compound obtained in step-b) from a suitable hydrocarbon solvent to provide pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7.
US 5932730 disclosed the process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid by using chiral resolving agent like L-proline methyl ester to provide the compound with less percentage of required isomer. Whereas, the present invention involves the usage of chiral reducing agent optionally in the presence of chiral catalyst provided more than 95 percent of the required isomer of the intermediate compound which enhanced the yield and purity of the ambrisentan. Hence the process of the present invention is more advantageous over the prior-art process.

In a preferred embodiment of the present invention provides an improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-5a with sodium hypochlorite in dichloromethane to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a,

b) reducing the keto compound of formula-6a with Borane-DMS in the presence of a R-Methyl CBS in toluene to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a,

c) optionally, purifying the compound obtained in step-b) from cyclohexane to provide pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a.
The fourth aspect of the present invention is to provide an improved process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid compound of formula-1, which comprising of the following steps: a) Reacting the benzophenone compound of formula-2,

Formula-2 with chloroacetic acid derivative compound of formula-3,

wherein 'R' is H or C1-12 alkyl;

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 in a suitable ether solvents selected from diisopropyl ether, dibutylether, methyl tert-butyl ether, dioxane and tetrahydrofuran to provide 3,3-diphenyloxirane-2-carboxylic acid derivative compound of formula-4,

wherein, R is H or C1-12 alkyl,

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 derivative compound of formula-5,

wherein, R is H or C1-12 alkyl, b) oxidizing the compound of formula-5 with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6,

wherein, R is H or C1-12 alkyl, c) reducing the keto compound of formula-6 with a suitable chiral reducing agent such as Borane THF or Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)( 1,3,2) oxaza - borolidine (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent like dichloromethane, toluene, xylene, THF or ethyl acetate to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7, d) reacting the compound of formula-7 with 4,6-dimethyl-2-(methylsulphonyl) pyrimidine compound of formula-8, in presence of a suitable base selected from alkali metal carbonates preferably potassium carbonate in a suitable solvent selected from polar aprotic solvents preferably dimethyl formamide followed by isolation of the compound by addition of water to provide (+)-(2S)-2-[(4,6-dimethyIpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid derivative compound of formula-9,

Formula-9 wherein, R is H or C1-12 alkyl, e) optionally, hydrolyzing the compound of formula-9 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,

f) optionally, purifying the compound obtained in step-e) in a suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropanol or mixtures thereof to provide pure (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid compound of formula-1.

The fifth aspect of the present invention is to provide an improved process for the preparation of Darusentan compound of formula-lb, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-5 with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-6,

b) reducing the keto compound of formula-6 with a suitable chiral reducing agent such as Borane THF or Borane-DMS optionally in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)( 1,3,2) oxazaborolidine (R-Methyl CBS) or R-Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent like dichloromethane, toluene, xylene, THF or ethyl acetate, preferably toluene to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid derivative compound of formula-7,

c) reacting the compound of formula-7 with 4,6-dimethoy-2-(methylsulphonyl) pyrimidine compound of formula-10 in presence of a suitable base preferably alkali metal carbonates like potassium carbonate in a suitable solvent preferably polar aprotic solvent such as dimethyl formamide to provide (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid derivative compound of formula-11,

d) optionally, hydrolyzing the compound obtained in step-c) in presence of 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 to provide Darusentan compound of formula-lb.

The present invention schematically represented as follows:

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 (80 ml) 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 and then methanol was distilled off completely. The reaction mixture cooled to 25-35°C and methanol (280 ml) was added to it. Para-toluene sulfonic acid (4 grams) was added to the above reaction mixture. The reaction mixture was stirred for 2 hours at 25-3 5 °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-oxo-3-methoxy-3,3-diphenyl propionic acid methyl ester (Formula-6a; R = CH3)

A solution of 2-hydroxy-3-methoxy-3,3-diphenyl propionic acid methyl ester compound of formula-5a (5 g) and dichloromethane (48 ml) was added to a mixture of 2,2,6,6-tetramethylpiperidinyloxide (0.007 g), potassium bromide (0.20 g) and dichloromethane (72 ml) at -15 to -5°C. Sodium hypochlorite solution (1.89 g) was basified using 10% sodium bicarbonate solution and added to the reaction mixture at -15 to -5°C and stirred for 15 minutes. After completion of the reaction, the reaction mixture was quenched with 10% sodium thiosulfate solution. Both dichloromethane and aqueous layers were separated and the dichloromethane layer was washed with water followed by sodium chloride solution and then distilled off the solvent to get title compound Yield: 4.95 g.

Example-3: Preparation of 2-oxo-3-methoxy-3,3-diphenyl propionic acid methyl ester (Formula-6a; R = CH3)

A solution of dimethylsulfoxide (3.32 g) and dichloromethane (5 ml) was added to a solution of oxalyl chloride (3.22 g) and dichloromethane (15 ml) at -75 to -70°C and stirred for 45 minutes at -75 to -70°C. A solution of 2-hydroxy-3-methoxy-3,3-diphenyl propionic acid methyl ester compound of formula-5a (5 g) and dichloromethane (10 ml) was added to the reaction mixture and stirred for 45 minutes at -75 to -70°C. Triethyl amine (7.9 g) was added to the reaction mixture at -75 to -70°C and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate solution. Both dichloromethane and aqueous layers were separated, the dichloromethane layer was washed with sodium bicarbonate solution followed by sodium chloride solution and then distilled off the solvent to get title compound. Yield: 4.16 g

Example-4: Preparation of 2-oxo-3-methoxy-3,3-diphenyl propionic acid methyl ester (Formula-6a; R = CH3)

A solution of Trichloroisocyanuric acid (1.76 g), potassium bromide (0.084 g) and dichloromethane (10 ml) was cooled to 0-5°C. A solution of 2-hydroxy-3-methoxy-3,3-diphenyl propionic acid methyl ester compound of formula-5a (2.0 g), dichloromethane (10 ml) and 2,2,6,6-tetramethylpiperidinyloxide (0.033 g) was added to the reaction mixture and stirred for 45 minutes at 0-5 °C. After completion of the reaction, the reaction mixture was filtered and filtrate was washed with dichloromethane, followed by 5% sodium bicarbonate, water and sodium chloride solution. Distilled off the solvent from the filtrate under reduced pressure to get title compound. Yield: 1.85 g

Example-5, 6 & 7: Preparation of 3-methoxy-2-oxo-3,3-diphenylpropanoic acid (Formula-6b; R = H)

The above compound of formula-6b can be prepared by repeating the process disclosed in examples 2, 3 and 4 by using 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid compound of formula-5b as the starting material.

Example-8: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (Formula-7a)

40 ml of toluene was taken in a round bottom flask and cooled to 0°C. To this added 2.66 g of Borane-dimethyl sulfide and 0.97 g of (R)-2-methyl-CBS oxazaborolidine under nitrogen atmosphere. To this reaction mixture slowly added 10 g of 2-oxo-3-methoxy-3,3-diphenyl propionic acid methyl ester compound of formula-6a dissolved in 10 ml of toluene. Stirred the reaction mixture for 3 hrs at 0-5°C. After completion of the reaction, the reaction mixture was quenched with water and then extracted with dichloromethane. The dichloromethane layer was distilled under reduced pressure. The obtained crude was isolated from cyclohexane (65 ml) to provide the title compound as a solid. Yield: 6.4g.

Example-9: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (Formula-7a)

A solution of 2-oxo-3-methoxy-3,3-diphenyl propionic acid methyl ester compound of formula-6a (20 g) and toluene (350 ml) was added drop wise to a pre-cooled solution of (-)-|3-chlorodiisopinocampheylborane (33.7 g) in toluene (300 ml) at -25°C. The reaction mixture was stirred overnight at 15°C. After completion of the reaction, the reaction mixture was quenched with water and then extracted with dichloromethane. The dichloromethane layer was distilled under reduced pressure. The obtained crude was isolated from cyclohexane (125 ml) to provide the title compound as a solid. Yield: 13 g.

Example-10 & 11: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (Formula-7b; R = H)

The above compound of formula-7b can be prepared by repeating the process disclosed in examples 8 & 9 by using 3-methoxy-2-oxo-3,3-diphenylpropanoic acid compound of formula-6b as the starting material.

Example-12: Preparation of (+)-(2S)-2-[(4,6-dimethyIpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid methyl ester (Formula-9a)

Mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a (50 g), dimethyl formamide (500 ml) and potassium carbonate (12 g) was stirred for 40 minutes at 25-35°C. 4,6-dimethyl-2-(methylsulphinyl) pyrimidine compound of formula-8 (34.5 g) was added and heated to 90-95°C and stirred for 4 hours. The reaction mixture was cooled to 25-35°C. Water (250 ml) was added and stirred for 60 minutes. The obtained solid was filtered, washed with water and then dried at 60-70°C to get the title compound. Yield: 55 g; MR: 130-140°C; S.O.R: +135.8° (C=0.5; MeOH)

Example-13: Preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid (Formula-1)

Aqueous sodium hydroxide solution (10 grams of NaOH in 250 ml of water) was added to the mixture of methanol (500 ml) and (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yi)oxy]-3-methoxy-3,3-diphenylpropanoic acid methyl ester compound of formula-9a (50 g) at 25-35°C, then heated to 85-90°C and stirred for 3 hours. The reaction mixture was cooled to 25-3 5°C and water (500 ml) was added. The reaction mixture was washed with ethyl acetate. The aqueous layer was acidified 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 below 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 title compound. Yield: 36 g.

Example-14: Preparation of (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid methyl ester (Formula-11a)

Mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a (50 g), dimethyl formamide (500 ml) and potassium carbonate (12 g) was stirred for 40 minutes at 25-35°C. 4,6-dimethoxy-2-(methylsulphonyl) pyrimidine compound of formula-10 (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 dimethyl formamide. 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 g M.R: 108-112°C; S.O.R: + 115° (O 0.5; MeOH)

Example-15: Preparation of (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid (Formula-lb)

Aqueous sodium hydroxide (5.59 g of NaOH 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-lla (30 g) 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 aqueous layer was acidified 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 obtained solid was filtered and washed with water. The solid was dried at 60-70°C to get the title compound. Yield: 27 g; M.R: 166-170°C; S.O.R: + 144.0° (C= 0.5; MeOH)

Claims:

1. A process for the preparation of 2-oxo-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-6

wherein, R is C1-12 alkyl,

comprising of, oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl
ester compound of formula-5

wherein, R is C1-12 alkyl,

with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-6.

2. A process for the preparation of 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a

comprising of oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-5a with a suitable oxidizing agent selected from sodium hypochlorite, trichloroisocyanuric acid, and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a.

3. An improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7

wherein, R is C1-12 alkyl,

comprising of, reducing the keto compound of formula-6 with a suitable chiral reducing agent selected from Borane THF or Borane-DMS in presence of a chiral catalyst selected from (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (1,2-c)( 1,3,2) oxazaborolidine (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride (Diisopinocampheyl chloroborane) in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7.

4. An improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a

comprising of, reducing the keto compound of formula-6a, with a chiral reducing agent such as Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)(l,3,2) oxazaborolidine (R-Methyl CBS) or R-Butyl CBS or R-Phenyl CBS in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a.

5. The process according to claim 1 to 4, wherein the solvent used is selected from dichloromethane, toluene, xylene, THF and ethyl acetate.

6. An improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7, formula-

wherein, R is C1-12 alkyl, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-5,

wherein, R is C1-12 alkyl,

with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenyl propionic acid alkyl ester compound of formula-6, b) reducing the keto compound of formula-6,

Formula-6 wherein, R is C1-12 alkyl,

with a chiral reducing agent such as Borane THF or Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-l H,3H-pyrrol (1,2-c)(l,3,2) oxazaborolidine (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7, c) optionally, purifying the compound obtained in step-b) from a suitable hydrocarbon solvent to provide pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7.

7. An improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-5a with a suitable oxidizing agent selected from sodium hypochlorite, trichloroisocyanuric acid and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-6a,

b) reducing the keto compound of formula-6a with a chiral reducing agent such as Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrol(l,2-c)(l,3,2)oxazaborolidine (R-Methyl CBS) or R-Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a,

c) optionally, purifying the compound obtained in step-b) from cyclohexane solvent to provide pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-7a.

8. A process for the preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid compound of formula-1, which comprising of the following steps: a) reacting the benzophenone compound of formula-2, with alkyl chloroacetate compound of formula-3, wherein 'R' is C1-12 alkyl; in presence of a suitable base selected from alkoxide base preferably sodium methoxide in a suitable ether solvents preferably tetrahydrofuran to provide 3,3-diphenyloxirane-2-carboxylic acid alkyl ester compound of formula-4, Formula-4 wherein, R is C1-12 alkyl, which on in-situ treatment with methanol in presence of a suitable acid selected
from para-toluene 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, wherein, R is C1-12 alkyl, b) oxidizing the alkyl ester compound of formula-5 with a suitable oxidizing agents selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite, oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-6, wherein, R is C1-12 alkyl,

c) reducing the keto compound of formula-6 with a suitable chiral reducing agent such as Borane-THF or Borane-DMS in the presence of a chiral catalyst such as (R)-tetrahydro-1 -methyl-3,3-diphenyl-lH,3H-pyrrol( 1,2-c)( 1,3,2) oxazaborolidine (R-Methyl CBS) or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent like dichloromethane, toluene, xylene, THF or ethyl acetate, preferably toluene to provide (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid alkyl ester compound of formula-7,

d) reacting the ester compound of formula-7 with 4,6-dimethyl-2-(methylsulphonyl) pyrimidine compound of formula-8, in presence of a suitable base selected from alkali metal carbonates preferably potassium carbonate in a suitable solvent selected from polar aprotic solvents

preferably dimethyl formamide followed by isolation of ester compound by addition of water to provide (+)-(2S)-2-[(4,6-dimethyIpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid alkyl ester compound of formula-9,
wherein, R is C1-12 alkyl,

e) hydrolyzing the ester compound of formula-9 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 the compound of formula-1 in a suitable ester solvent like ethyl acetate, methyl acetate and propyl acetate,

f) optionally, purifying the compound obtained in step-e) in a suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropanol or mixtures thereof to provide pure (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid compound of formula-1.

9. An improved process for the preparation of Darusentan compound of formula-lb, which comprising of,

a) oxidizing the 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-5 with a suitable oxidizing agent selected from chromic acid, potassium dichromate, trichloroisocyanuric acid, sodium hypochlorite and oxalyl chloride in a suitable solvent to provide 2-oxo-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-6,

b) reducing the keto compound of formula-6 with a suitable chiral reducing agent With a chiral reducing agent such as Borane-THF or Borane-DMS in the presence of a chiral catalyst such as R-Methyl CBS or R- Butyl CBS or R-Phenyl CBS or with DIP Chloride in a suitable solvent like dichloromethane, toluene, xylene, THF or ethyl acetate, preferably toluene to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid alkyl ester compound of formula-7,

c) reacting the ester compound of formula-7 with 4,6-dimethoy-2-(methylsulphonyl) pyrimidine compound of formula-10 in presence of a suitable base preferably alkali metal carbonates like potassium carbonate in a suitable solvent preferably polar aprotic solvent such as dimethyl formamide to provide (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid alkyl ester compound of formula-11,

d) hydrolyzing the compound obtained in step-c) in presence of a suitable aqueous base in a suitable solvent to provide Darusentan compound of formual-lb.

10. A compound having the following structural formula: