Improved Process for the Preparation of Ambrisentan and Its Novel

Amine salts

Field of the Invention:
The present invention relates to an improved process for the preparation of ambrisentan. The present invention also relates to novel amine salts of ambrisentan and its intermediate as well as process for their preparation. Ambrisentan is chemically known as (+)-{25)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid, which is represented by the following 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 comprises 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.

Drugs of future 2005, 30(8), 765-770 discLosed the process for the preparation of racemic ambrisentan. The disclosed process comprises the reaction of 2-hydroxy-3-methoxy-3,3-diphenyl propionic 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.

The above process involves the usage of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester for the condensation with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine to provide ester derivative of ambrisentan, which is hydrolyzed to get the ambrisentan. But the process is time taking and involves additional steps like esterification and later the hydrolysis of the ester group.

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)-1 -(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-dimethyI-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. 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.

Hence the focus of the present invention is to overcome the drawbacks of prior art and to provide an improved process for the preparation of ambrisentan and its novel amine salts.

Also to prepare salts of intermediates using them to prepare ambrisentan, in order to get ambrisentan of higher purity, which can be utilized in a commercial scale. Present invention utilizes a mild base in the place of a strong base like lithium amide in the condensation step which is easier to handle and use in scale up process.

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 reacting the (S)-2-hydroxy-3-melhoxy-3,3-diphenylpropionic acid compound of formula-2 with 4,6-dimethyl-2-{methyIsulphonyl)pyrimidine compound of formula-3 in the presence a suitable base in a suitable solvent to provide ambrisentan compound of formula-1.

The second aspect of the present invention is to provide novel amine salt of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compounds of general formula-4.

The third aspect of the present invention is to provide novel amine salt of ambrisentan compounds of general formula-5.

The fourth aspect of the present invention is to provide a process for the preparation of high pure ambrisentan compound of formula-1, through the novel amine salt compounds of general formula-5.

The fifth aspect of the present invention is to provide a process for the preparation of {S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of fomula-2, which comprises of the following steps;

a) treating the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with R(+)-phenyl ethyl amine in a suitable solvent to provide the R(+)-phenyl ethyl amine saltof (S)-2-hydroxy-3-meUioxy-3,3-tiiphenylpropionic acid compound of formuia-4,

b) treating the amine salt compound of formula-4 with a suitable acid in a suitable solvent to provide the compound of formula-2.

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.

• Provides novel amine salts of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and ambrisentan, which are used to prepare a high pure ambrisentan.

• Provides an improved process with the usage of a simple base such as sodium hydroxide and avoids the usage of amide bases such as lithium amide.

Detailed Description of the Invention;

As used herein the term "ester solvents" refers to ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" refers to tetrahydroturan, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" refers to toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" refers to 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;

As used herein the term "inorganaic acid" refers to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and HCIO4.

As used herein the term "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 present invention relates to an improved process for the preparation of ambrisentan and its intermediates through a novel amine salts. Ambrisentan is chemically known as (+)-(2iS)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl propanoic acid represented by compound of formula-1.


Fonnula-3 in the presence of a suitable base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and alkoxides such as sodium tert-butoxide, potassium tert-butoxide; and LiHMDS, preferably sodium hydroxide, in a suitable solvent selected from a group consisting ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents; chloro solvents; water and mixtures thereof, preferably ether solvents, followed by isolation from a suitable hydrocarbon solvent, to provide ambrisentan compound of formula-1.

The second aspect of the present invention provides novel amine salt of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compounds of general formula-4 having the following structure.

The term "amine salt" of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compounds of general formula-4 refers to amine salt, in which the amine residue has a formula NR1R2R3 wherein independently R1,R2 and R3 are H, straight or branched chain C1-15 alkyl or hydroxyalkyl, C3-10 single or fused ring optionally substituted cycloalkyl, independently R1, R2 and R3 can combine with each other to form a C1 membered cycloalkyl ring or heterocyclic residue containing one or more heteroatom (selected from S, N or O). The amines which are of specific interest are monomethylamine, ethyl amine, n-propylamine, isopropylamine, n-butylamine, 2-butylamine, tertiary butyl amine cyclohexyl amine, dicyclohexyl amine, benzyl amine, R-phenyl ethyl amine and the like.

The present invention also provides a process for the preparation of novel amine salt compounds of general formula-4, which comprises of reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-2,

with a suitable amine of formula NR1R2R3 as defined above, in a suitable solvent selected from a group consisting of but not limited to ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents; chloro solvents; water and mixtures thereof, preferably ester solvents to provide the corresponding amine salt compounds of general fonnula-4.

The third aspect of the present invention provides novel amine salt of ambrisentan compounds of general formula-5 represented by the following structure.

The novel amine salt of ambrisentan compounds of general formula-5 of the present invention refers to amine salt, in which the amine residue has a formula NR1R2R3 where in independently R1,R2 and R3 are H, straight or branched chain C[-is alkyl or hydroxyalkyl, C3-10 single or fused ring optionally substituted cycloalkyl, independently R1, R2 and R3 can combine with each other to form a C3.7 membered cycloalkyl ring or heterocyclic residue containing one or more heteroatom (selected from S, N or O). The amines which are of specific interest are monomethylamine, ethyl amine, n-propylamine, isopropylamine, n-butylamine, 2-butylamine, tertiary butyl amine cyclohexyl amine, dicyclohexyl amine, benzyl amine, R-phenyl ethyl amine and the like.

The present invention also provides a process for the preparation of novel amine salt of ambrisentan compounds of general formula-5, which comprises of reacting the ambrisentan compound of formula-1

Formula-1 with a suitable amine of formula NR1R2R3 as defined above, In a suitable solvent selected from a group consisting of but not limited to ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents; chloro solvents; water and mixtures thereof, preferably ester solvents to provide corresponding amine salt compounds of formula-5.

The novel amine salt compounds of general fonnula-4 & 5 of the present invention are used to prepare a high pure ambrisentan.

The fourth aspect of the present invention provides a process for the preparation of high pure ambrisentan compound of formula-l through the novel amine salt compounds of general formula-S, which comprises of treating the crude ambrisentan with a suitable amine of formula NR1R2R3 as defined above, in a suitable solvent selected from a group consisting of but not limited to ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents; chloro solvents; water and mixtures thereof, to provide the corresponding amine salt compounds of general formula-5, which comprises of treating the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with R(+)-phenyl ethyl amine in a suitable solvent selected from a group consisting of but not limited to ether solvents, ester solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, hydrocarbon solvents, chloro solvents; water and mixtures thereof, preferably chloro solvents, to provide the R(+)-phenyl ethyl amine salt of (S)- 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-4A,


The amines salt compounds of general formula-6 and 6a of the present invention can be prepared in a similar manner as per the process disclosed in third aspect of the present invention. These amine salts of the present invention are used as an intermediate for the preparation of high pure ambrisentan.

The present invention also provides novel amine salt of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compounds of general formula-7 and its R isomer compounds of general formula-7a having the following structure.


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 ambrisentan compound of formula-1:

(S)-2-hydroxy'3-methoxy-3,3-diphenylpropionic acid (15 grams in 15 ml THF) was added to a solution of lithium hexamethyldisilazide (115 ml) (20% solution in tetahydrofuran) at 10-15°C and stirred for 10 minutes. 4,6-dimethyl-2-(methylsulphonyl)pyrimidine (10.5 grams in 15 ml of tetarhydrofuran) was added to the reaction mixture and heated to 40-45°C then stirred for 10 hours. The reaction mixture was cooled and then quenched with water. The aqueous and organic layers were separated, the aqueous layer was acidified with hydrochloric acid and then the reaction mixture extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off partially under reduced pressure. The reaction mixture was cooled to 10-15°C and stirred for 30 minutes. The solid obtained was filtered, washed with ethyl acetate and then dried to get the title compound. Yield:
13.5 grams S.O.R:+161.07°

Example-2: Preparation of ambrisentan compound of formula-l:

(S)-2-hydroxy-3-methoxy-3,3-diphenyIpropionic acid (20 grams in 20 ml of THF) was added to a mixture of sodium hydroxide (8.5 grams) and tetahydrofuran (110 ml) and stirred for 20 minutes at 25-35°C. 4,6-dimethyl-2-(methyIsulphonyl)pyrimidine (19 grams) was added to the reaction mixture and heated to 40-45°C then stirred for 24 hours.

The reaction mixture was cooled to 25-35°C and quenched with water then washed with cyclohexane. The reaction mixture was acidified with hydrochloric acid and then extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off completely under reduced pressure. The reaction mixture was cooled to 25-35°C, cyclohexane (100 ml) was added to it and then heated to 60-65°C. The reaction mixture was cooled to 25-30°C and stirred for 45 minutes. The solid obtained was filtered, washed with cyclohexane and then dried to get the title
compound.

Yield: 19 grams

S.O.R; + 144.87° (C = 0.5 in MeOH)
Exaniple-3: Preparation of ambrisentan compound of formula-l:

The title compound prepared analogues manner to exampIe-2 except that the sodium tertiary butoside (2.2 grams) was used in the place of sodium hydroxide for 5 grams of {S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. Yield: 2.5 grams M.R: 188-192°C
Example-4: Preparation of (S)-2-hydroxy-3-methoxy-33-diphenylpropionic acid:

R(+)-phenyl ethyl amine (11.12 grams) was added to a solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (25 grams) and chloroform (25 ml) at 40°C and stirred for 30 minutes. The reaction mixture was cooled, and the solid obtained was filtered and washed with chloroform. Ethyl acetate (50 ml) and water (50 ml) was added to the obtained solid and then the reaction mixture was acidified with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with ethyl acetate. The solvent from combined organic layer was distilled off completely under reduced pressure at below 60°C. The obtained residue was dissolved in toluene (30 ml) at 60-70°C and then cooled to 25-30°C. The solid was filtered, washed with toluene and then dried to get the title compound. Yield: 5.5 grams S.O.R: + 28.32°

Example-5: Preparation of (S)-2-hydroxy-3-methoxy-33-diphcnyIpropionlc acid:

The title compound prepared analogues manner to example-4 except that 8.89 grams of R(+)-phenyl ethyl amine is used instead of 11.85 grams. Yield: 6.0 grams S.O.R:+27.0°

Example-6: Preparation of tertiary butyl amine salt of (S)-2-hydroxy-3-methoxy-33-diphenyIpropionic acid:

A solution of tertiary butyl amine (1.61 grams) in ethyl acetate (5 ml) was added to a solution of (S)-2'hydroxy-3-methoxy-3,3-diphenylpropionic acid (5 grams) in ethyl acetate (20 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 6.5 grams M.R:210-216°C-Ba Purity by HPLC: 99.77 %

ExampIe-7: Preparation of monomethylamlne salt of (S)-2-hydroxy-3-methoxy-33-diphenylproptonic acid:

A solution of monomethylamlne (3.46 grams) in ethyl acetate was added to a solution of (S)-2-hydroxy-3-methoxy-3,3-tiiphetiylpcopionic acid (10 grams) in ethyl acetate (50 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 8.5 grams M.R; 196-198°C Purity by HPLC: 99.89 %

ExampIe-8: Preparation of dicyclohexaylamine salt of (S)-2-hydroxy-3-methoxy-3»3-diphenylpropionic acid:

A solution of dicyclohexylamine (3.99 grams) in ethyl acetate was added to a solution of (S)-2-hydroxy-3-methoxy-33-diph6nylpropvonic acid (5 grams) in ethyl acetate (25 ml) at 25-30°C and stirred for 45 minutes. The solid formed is filtered, washed with ethyl acetate and then dried to get the title compound Yield: 7.5 grams M.R-. 190-194''C

Example-9; Preparation of R(+)-phenyl ethylamine salt of (S)-2-hydroxy-3-methoxy-33-diphenylpropionic acid:

A solution of R(+)-phenyl ethylamine (2.0 grams) in ethyl acetate was added to a solution of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (5 grams) in ethyl acetate (40 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 7.0 grams M.R;I80-I84°C Purity by HPLC: 99.78%

Example-10: Preparation of dicyclohexylaniine salt of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid:

A solution of dicyclohexylamine (2.87 grams) in ethyl acetate was added to a solution of ambrisentan (5 grams) in ethyl acetate (20 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 2 grams; M.R: 180-184°C Purity by HPLC: 99.01%

Example-11: Preparation of monomethylamine salt of (+)-(25)-2-{(4,6-dimethylpyrimidin-2-yl)oxy]-3-niethoxy-3^-diphenylpropanoicacid:

A solution of monomethylamine (0.48 grams) in ethyl acetate was added to a solution of ambrisentan (5 grams) in ethyl acetate (25 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 2.5 grams; M.R: 188-192°C Purity by HPLC: 99.00 %

£xample-12: Preparation of tertiarybutylamine salt of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yI)oxyJ-3-methoxy-3,3-diphenyIpropanoic acid:

A solution of teriarybutylamine (1.158 grams) in ethyl acetate was added to a solution of ambrisentan (5 grams) in ethyl acetate (35 ml) at 25-30°C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 5.0 grams; M.R: 198-206°C Purity by HPLC: 99.50%

ExampIe-13: Preparation of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yI)oxy]-3-niethoxy-33-diphenylpropanoic acid from amine salt:

Monomethyl amine salt of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid (1.5 grams) was taken in water (6 ml) and acidified it using hydrochloric acid at 25-30°C. The reaction mixture was stirred for 90 minutes at 25-30°C. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 1.2 grams

Exampie-14: Preparation of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yI)oxy]-3-methoxy-33-diphenyIpropanoic acid:

Tert-butyl amine salt of (+)-(25)-2-[(4,6-dimethylpyrimidin-2-yI)oxy]-3-methoxy-3,3-diphenylpropanoic acid (3.0 grams) was taken in water (12 grams) and acidified it using hydrochloric acid. The reaction mixture stirred for 90 minutes at 25-3Q°C. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 2.6 grams

We Claim:

1. An improved process for the preparation of ambrisentan compound of formula-1,

Which comprises of reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-2,

With 4,6-dimethyl-2-(methylsulphonyl)pyrimidine compound of formula-3

in the presence a suitable base selected from alkali hydroxides such as sodium hydroxide, potassium hydroxide, and tert-butoxide such as sodium tert-butoxide, potassium tert-butoxide; and LiHMDS, in a suitable solvents selected from ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate; and mixtures thereof, followed by isolation from a suitable hydrocarbon solvents selected from toluene, hexane, heptane and cyclohexane to provide ambrisentan compound of formula-1.

2. Novel amine salt of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropiomc acid compounds of general formula-4 having the following structure.


wherein R1,R2 and R3 are independently selected from H, straight or branched chain C1-15 alkyl or hydroxyalkyl, C3-10 single or fused ring optionally substituted cycloalkyl, independently R1, R2 and R3 can combine with each other to form a C3-7 membered cycloalkyl ring or heterocyclic residue containing one or more heteroatom (selected from S, N or O), specifically monomethylamine, ethyl amine, n-propylamine, isopropylamine, n-butylamine, 2-butylamine, tertiary butyl amine cyclohexyl amine, dicyclohexyl amine, benzyl amine and R-phenyl ethyl amine.

3. Novel amine salt of ambrisentan compounds of general fonnula-5 having the following structural formula.


5. A process for the preparation of novel amine salt compounds of general formula-
4, which comprises of reacting the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic
acid compound of formula-2, with a suitable amine of formula NR1R2R3 as defined above, in a suitable solvent selected from a group consisting of but not limited to ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents: chloro solvents; water and mixtures thereof, to provide the corresponding amine salt compounds of general formula-4.

6. A process for the preparation of novel amine salt compounds of general formula-5, which comprises of reacting the compound of ambrisentan compound of formula-1 with a suitable amine of formula NR1R2R3 as defined above, in a suitable solvent selected from a group consisting of but not limited to ether solvents; ester solvents; polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents; chloro solvents; water and mixtures thereof, to provide conesponding amines salt compounds of general formula-5.

7. A process according to claim 5 & 6, wherein the amine salt is selected from selected from monomethylamine, ethyl amine, n-propylamine, isopropylamine, n-butylamine, 2-butyiamine, tertiary butyl amine cyclohexyl amine, dicyclohexyl amine, benzyl
amine and R-phenyl ethyl amine.

8. An improved process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-2, which comprises of the following steps;
a) treating the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with R(+)-phenyl ethyl amine, in a suitable solvent selected from chloro solvents; ester solvents; water and mixtures thereof to provide the R(+)-phenyl ethyl amine salt of (S)- 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formu]a-4A,



b) treating the obtained ambrisentan compound of formula-1 with a suitable amines
selected from monomethylamine, ethyl amine, n-propylamine, isopropylamine, n-
butylamine, 2-butylamiiie, tertiary butyl amine cyclohexyl amine, dicyclohexyl
amine, benzyl amine and R-phenyl ethyl amine in a suitable ester solvents
selected from ethyl acetate, methyl acetate, isopropyi acetate and mixtures thereof
to provide the corresponding amine salt compounds of general formula-5,

c) treating the amine salt compounds of general formula-5 with a suitable organic or
inorganic acid in a suitable solvent selected from ether solvents; ester solvents;
polar aprotic solvents; ketone solvents; alcoholic solvents; hydrocarbon solvents;
chloro solvents; water and mixtures thereof to provide the high pure ambrisentan
compound of formula-1.

10. A process according to claim 8 &9, wherein the inorganic acid used is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and HC104 and organic acid used is selected from formic acid, acetic acid, oxalic acid, maleic acid, citric acid, propionic acid, p-toluene sulphonic acid, methane sulphonic acid and benzene sulphonic acid.